JP2013040215A - Stable emulsion composition - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide an emulsion composition having improved stability.SOLUTION: The invention provides an emulsion composition comprising (A) a compound stable in an acidic range, and (B) a buffer, wherein the pH is adjusted from about 3.7 to about 5.5.

Description

  The present invention relates to an emulsified composition having improved stability.

(Background of the Invention)
In WO99 / 46224, the formula (i):

[Wherein, R represents an aliphatic hydrocarbon group which may have a substituent, an aromatic hydrocarbon group which may have a substituent, a heterocyclic group which may have a substituent, a formula : -OR ¹ (wherein R ¹ represents a hydrogen atom or an aliphatic hydrocarbon group which may have a substituent) or a group represented by the formula:

(Wherein R ^1b represents a hydrogen atom or an aliphatic hydrocarbon group which may have a substituent, and R ^1c is the same as or different from R ^1b and represents an aliphatic hydrocarbon group which may have a hydrogen atom or a substituent. R ⁰ represents a hydrogen atom or an aliphatic hydrocarbon group, or R and R ⁰ together represent a bond, and ring A represents (1) a substituent. (2) an aromatic hydrocarbon group which may have a substituent, (3) formula: —OR ¹ (wherein R ¹ is as defined above) And (4) a cycloalkene substituted with 1 to 4 substituents selected from halogen atoms, Ar represents an aromatic hydrocarbon group which may have a substituent. ,
formula:

The group represented by the formula:

Or

N represents an integer of 1 to 4. A compound represented by
(Ii) Formula:

[Wherein, R ^a is an aliphatic hydrocarbon group which may have a substituent, an aromatic hydrocarbon group which may have a substituent, a heterocyclic group which may have a substituent, A group represented by the formula: —OR ^1a (wherein R ^1a represents a hydrogen atom or an aliphatic hydrocarbon group which may have a substituent) or a formula:

Wherein R ^1a is as defined above, and R ^1b is the same as or different from R ^1a and represents a hydrogen atom or an aliphatic hydrocarbon group which may have a substituent. R ^0a represents a hydrogen atom or an aliphatic hydrocarbon group, or R ^a and R ^0a together form a bond, Ar ^a represents an optionally substituted aromatic hydrocarbon group, :

The group represented by

Or

N represents an integer of 1 to 4. Or a salt or prodrug thereof has an inhibitory effect on nitric oxide (NO) production and an inhibitory action on the production of inflammatory cytokines such as TNF-α, IL-1, and IL-6. It is described as being useful as a preventive / therapeutic agent for diseases such as heart disease, autoimmune disease, inflammatory disease, central nervous system disease, infectious disease, sepsis, septic shock and the like.

  The publication discloses that the compound is dissolved, suspended or emulsified in vegetable oil or propylene glycol to produce an oily injection (WO99 / 46242 pamphlet).

WO01 / 10826 includes
formula:

[Wherein, R ¹ represents an aliphatic hydrocarbon group which may have a substituent, an aromatic hydrocarbon group which may have a substituent, a heterocyclic group which may have a substituent, A group represented by the formula: —OR ^1a (wherein R ^1a represents a hydrogen atom or an aliphatic hydrocarbon group which may have a substituent), or a group represented by the formula:

Wherein R ^1b and R ^1c are the same or different and each represents a hydrogen atom or an aliphatic hydrocarbon group which may have a substituent. X represents a methylene group, nitrogen An atom, a sulfur atom or an oxygen atom, Y represents a methylene group which may have a substituent or a nitrogen atom which may have a substituent, and ring A may have (1) a substituent A good aliphatic hydrocarbon group, (2) an aromatic hydrocarbon group which may have a substituent, (3) a formula: —OR ² (wherein R ² has a hydrogen atom or a substituent) An aliphatic hydrocarbon group which may be substituted) and (4) a 5- to 8-membered ring which may be further substituted with 1 to 4 substituents selected from halogen atoms, Ar is The aromatic hydrocarbon group which may have a substituent is represented by the formula:

The group represented by the formula:

Or the formula:

M represents an integer of 0 to 2, n represents an integer of 1 to 3, and the sum of m and n is 4 or less. However, when X is a methylene group, Y represents a methylene group which may have a substituent. Or a prodrug thereof has a nitric oxide (NO) production inhibitory action and a inflammatory cytokine production inhibitory action such as TNF-α, IL-1, and IL-6, It is described that it is useful as a prophylactic / therapeutic agent for diseases such as heart disease, autoimmune disease, inflammatory disease, central nervous system disease, infectious disease, sepsis, septic shock, etc. (WO01 / 10826). Issue pamphlet).

  An object of the present invention is to provide an emulsified composition containing a compound that is stable in the acidic region typified by the above compound with further improved stability.

  In the present specification, a compound that is stable in the acidic region means that in the neutral or basic region where the pH exceeds about 6, decomposition of the compound or generation of an analog is likely to occur, while the acidic region (pH of about 6 or less). ) Is a collective term for a group of compounds that are less likely to decompose or generate analogs and have high compound stability. More specifically, a compound that is stable in the acidic region refers to a compound that is stored in the same storage conditions (temperature, humidity, period, etc.) in the acidic region and the compound in the neutral or basic region. The quality of the product is investigated, and the compound with less decomposition and generation of analogs in the acidic region. These compounds, or compositions containing them, are stable when stored in the acidic region, but are unstable in the neutral and basic regions, so there are difficulties in storage and use in these regions. It was. For example, when a compound stable in the above acidic region is used as an emulsion composition, since the emulsion composition is generally stable in a neutral region, the stable region of the compound and the stable region of the emulsion composition are coincident. Therefore, it was difficult to obtain a composition having excellent stability. When emulsifying a stable compound under an acidic region and preparing an emulsion composition in a neutral range, a stable composition cannot be obtained because the compound decomposes, and when an emulsion composition in an acidic region is prepared, When the emulsified composition is autoclaved or stored for a long period of time, phospholipids blended as an emulsifier in the emulsified composition mainly decompose, and free fatty acids are generated by the decomposition, resulting in the pH of the emulsified composition. Decreases and the stability of the emulsion composition also decreases. Furthermore, there has been a problem that decomposition of the emulsion composition is promoted by lowering the pH.

  In addition, Washington et al. (Advanced Drug Delivery Reviews 20, 131-145, 1996) describes that the addition of an electrolytic substance to an emulsion composition decreases the stability of the emulsion composition. It is known that an electrolyte such as a buffering agent is not added as much as possible.

  In light of the above problems, the present inventors have conducted extensive research, and as a result, an emulsion composition having a pH of about 3.7 to about 5.5 containing a stable compound and buffer in the acidic region. However, the present inventors have unexpectedly found that the pH does not fluctuate during high-pressure steam sterilization or storage for a long period of time, exhibit extremely good stability, and exhibit excellent medicinal effects. As a result of further investigation based on this finding, the present inventors have completed the present invention.

That is, the present invention is as follows.
[1] An emulsified composition having a pH adjusted to about 3.7 to about 5.5, comprising (A) a compound stable in the acidic region and (B) a buffering agent.
[2] The composition according to [1], further containing an anionic synthetic phospholipid as an emulsifier.
[3] (A) A compound stable in the acidic region is represented by the formula (a):

[Wherein, R represents an aliphatic hydrocarbon group which may have a substituent, an aromatic hydrocarbon group which may have a substituent, a heterocyclic group which may have a substituent, a formula : -OR ¹ (wherein R ¹ represents a hydrogen atom or an aliphatic hydrocarbon group which may have a substituent) or a group represented by the formula:

(Wherein R ^1b represents a hydrogen atom or an aliphatic hydrocarbon group which may have a substituent, and R ^1c is the same as or different from R ^1b and represents an aliphatic hydrocarbon group which may have a hydrogen atom or a substituent. R ⁰ represents a hydrogen atom or an aliphatic hydrocarbon group, or R and R ⁰ together represent a bond, and ring A ¹ represents (1) substitution. An aliphatic hydrocarbon group which may have a group, (2) an aromatic hydrocarbon group which may have a substituent, and (3) a formula: —OR ¹ (wherein R ¹ is as defined above) And (4) a cycloalkene which may be substituted with 1 to 4 substituents selected from halogen atoms, Ar is an aromatic group which may have a substituent. The hydrocarbon group has the formula:

The group represented by the formula:

Or

N represents an integer of 1 to 4. Or a compound represented by formula (b):

[Wherein, R ^{1 ′} represents an aliphatic hydrocarbon group which may have a substituent, an aromatic hydrocarbon group which may have a substituent, or a heterocyclic group which may have a substituent. A group represented by the formula: —OR ^{1a ′} (wherein R ^{1a ′} represents a hydrogen atom or an aliphatic hydrocarbon group which may have a substituent), or a formula:

Wherein R ^{1b ′} and R ^{1c ′} are the same or different and each represents a hydrogen atom or an aliphatic hydrocarbon group which may have a substituent. X represents a methylene group. , A nitrogen atom, a sulfur atom or an oxygen atom, Y is a methylene group which may have a substituent or a nitrogen atom which may have a substituent, and ring A has (1) a substituent An aliphatic hydrocarbon group which may be substituted, (2) an aromatic hydrocarbon group which may have a substituent, (3) Formula: —OR ^{2 ′} (wherein R ^{2 ′} is a hydrogen atom or a substituent) And an aliphatic hydrocarbon group which may have a substituent.) And (4) a 5- to 8-membered ring which may be further substituted with 1 to 4 substituents selected from a halogen atom. Ar ′ represents an aromatic hydrocarbon group which may have a substituent, represented by the formula:

The group represented by the formula:

Or the formula:

M represents an integer of 0 to 2, n ′ represents an integer of 1 to 3, and the sum of m and n ′ is 4 or less. However, when X is a methylene group, Y represents a methylene group which may have a substituent. Or a salt thereof or a prodrug thereof, the composition according to any one of [1] or [2] above.

  [4] The compound represented by the formula (I) is ethyl (6R) -6- [N- (2-chloro-4-fluorophenyl) sulfamoyl] cyclohex-1-ene-1-carboxylate, d-ethyl 6- [N- (2,4-difluorophenyl) sulfamoyl] cyclohex-1-ene-1-carboxylate, ethyl 6- [N- (2-chlorophenyl) sulfamoyl] cyclohex-1-ene-1-carboxylate, or ethyl The composition according to [3] above, which is 6- [N- (2-chloro-4-methylphenyl) sulfamoyl] cyclohex-1-ene-1-carboxylate.

  [5] Either of the above [1] or [2], wherein the buffer is one or more buffers selected from the group consisting of acetate buffer, lactate buffer, citrate buffer, and phosphate buffer A composition according to 1.

  [6] The composition of the above-mentioned [5], wherein the acetate buffer is acetic acid and sodium acetate.

  [7] The emulsion composition according to any one of [1] or [2] above, wherein the concentration of the buffering agent is 100 mM or less.

  [8] The composition according to [1] above, further comprising a component selected from the group consisting of an oil component, an emulsifier, water and a mixture thereof.

  [9] The composition of the above-mentioned [8], which is an oil-in-water type.

  [10] The composition according to any one of the above [1] or [2], comprising a dispersed phase particle containing a compound stable in an acidic region, an oil component and an emulsifier, and water in which the dispersed phase particle is dispersed. object.

  [11] The composition according to the above [10], wherein the dispersed phase particles have an average particle size of about 0.025 to about 0.7 μm.

  [12] The composition according to [10] above, wherein the dispersed phase particles and the water in which the dispersed phase particles are dispersed are stable without phase separation.

  [13] The composition according to the above [9], which does not contain visible oil droplets.

  [14] The composition of the above-mentioned [8], wherein the oil component is vegetable oil.

  [15] The composition of the above-mentioned [14], wherein the vegetable oil is soybean oil.

  [16] The composition of the above-mentioned [8], wherein the emulsifier is a phospholipid.

  [17] The composition of the above-mentioned [16], wherein the phospholipid is egg yolk lecithin or phosphatidylglycerol.

  [18] The composition described in [2] above, wherein the anionic synthetic phospholipid is phosphatidylglycerol.

  [19] The composition of the above-mentioned [8], wherein the amount of the oil component is about 1 to about 30% by weight based on the whole composition.

  [20] The composition described in [8] above, wherein the amount of the emulsifier is about 0.1 to about 10% (W / V) based on the whole composition.

  [21] The composition according to any one of [17] or [18] above, wherein the phosphatidylglycerol is dimyristoyl phosphatidylglycerol.

  [22] The composition of the above-mentioned [8], comprising soybean oil, egg yolk lecithin, glycerin and water.

  [23] The composition according to any one of [1] or [2], which is for injection.

  [24] The composition according to any one of [1] or [2] above, which contains about 0.001 to about 95% by weight of a compound stable in the acidic region relative to the whole composition.

  [25] A method for producing an emulsified composition comprising (A) a compound that is stable in an acidic region and (B) a buffer, wherein the pH is adjusted to about 3.7 to about 5.5. A method for producing the composition.

  [26] The production method of the above-mentioned [25], wherein the emulsion composition further contains an anionic synthetic phospholipid as an emulsifier.

  [27] The production method of the above-mentioned [25], wherein the stability of the pH of the emulsion composition and the particle size of the dispersed phase particles during autoclave sterilization is improved.

  [28] A method for long-term stabilization of an emulsified composition, wherein the emulsified composition contains (A) a compound that is stable in the acidic region and (B) a buffer, and the pH of the emulsified composition is about 3 A long-term stabilization method comprising adjusting to .7 to about 5.5.

  [29] The long-term stabilization method according to [28], further comprising adding an anionic synthetic phospholipid as an emulsifier to the emulsion composition.

The present invention further provides the following.
[30] The composition according to any one of [1] or [2] above, which is a nitric oxide or / and cytokine production inhibitor, or a TLR signal inhibitor.

  [31] The above [1], which is a therapeutic agent for heart disease, autoimmune disease, sepsis, septic shock, severe sepsis, organ damage, sepsis, endotoxin shock, shock, inflammatory disease, central nervous system disease or infectious disease Or the composition in any one of [2].

  [32] A cardiac disease, autoimmune disease, sepsis, which comprises administering a pharmacologically effective amount of the composition according to any one of [1] or [2] above to a mammal in need thereof A method for treating septic shock, severe sepsis, organ damage, sepsis, endotoxin shock, shock, inflammatory disease, central nervous system disease or infectious disease.

  [33] To produce a prophylactic / therapeutic agent for heart disease, autoimmune disease, sepsis, septic shock, severe sepsis, organ damage, sepsis, endotoxin shock, shock, inflammatory disease, central nervous system disease or infectious disease Of the above-mentioned [1] or [2].

[34] In formula (I), R may be substituted with 1 to 3 substituents selected from (1) (i) C _1-4 alkyl, hydroxy, oxo and C _1-4 alkoxy. A 5- to 8-membered ring group containing 1 to 4 heteroatoms selected from a nitrogen atom (which may be oxidized), an oxygen atom and a sulfur atom, or a condensed ring group thereof, (ii) an oxo group, (iii) Hydroxyl group, (iv) C _1-6 alkoxy group, (v) C _3-10 cycloalkyloxy group, (vi) C _6-10 aryloxy group, (vii) C _7-19 aralkyloxy group, (viii) C _A nitrogen atom (which may be oxidized), an oxygen atom and a sulfur atom which may be substituted with 1 to 3 substituents selected from _1-4 alkyl, hydroxy, oxo and C _1-4 alkoxy 5- to 8-membered ring containing 1 to 4 heteroatoms selected from Gowa - oxy group, (ix) C _1-6 alkylthio group (the sulfur atom may be oxidized), (x) C _3-10 cycloalkylthio group (the sulfur atom be oxidized (Xi) C _6-10 arylthio group (the sulfur atom may be oxidized), (xii) C _7-19 aralkylthio group (the sulfur atom may be oxidized), (xiii) a nitrogen atom (which may be oxidized), oxygen, which may be substituted with 1 to 3 substituents selected from C _1-4 alkyl, hydroxy, oxo and C _1-4 alkoxy 5- to 8-membered ring containing 1 to 4 heteroatoms selected from an atom and a sulfur atom, or a condensed ring-thio group thereof, (xiv) C _1-4 alkyl, hydroxy, oxo and C _1-4 alkoxy Substituted with 1 to 3 substituents Or, a nitrogen atom (optionally oxidized), 5-8 membered ring or a condensed ring heteroatoms containing 1-4 selected from oxygen atom and a sulfur atom - sulfinyl group, (xv) C _1- Selected from nitrogen atom (which may be oxidized), oxygen atom and sulfur atom which may be substituted with 1 to 3 substituents selected from ₄ alkyl, hydroxy, oxo and C _1-4 alkoxy 5- to 8-membered ring containing 1 to 4 heteroatoms or a condensed ring thereof-sulfonyl group, (xvi) nitro group, (xvii) halogen atom, (xviii) cyano group, (xix) carboxyl group, (xx) C _1-10 alkoxy-carbonyl group, (xxi) C _3-6 cycloalkyloxy-carbonyl group, (xxii) C _6-10 aryloxy-carbonyl group, (xxiii) C _7-19 aralkyloxy-carbonyl group, (xxiv) ) C _1-4 a Selected from a nitrogen atom (which may be oxidized), an oxygen atom and a sulfur atom, which may be substituted with 1 to 3 substituents selected from alkyl, hydroxy, oxo and C _1-4 alkoxy 5- to 8-membered ring containing 1 to 4 heteroatoms or a condensed ring thereof-oxycarbonyl group, (xxv) C _6-10 aryl-carbonyl group, (xxvi) C _1-6 alkanoyl group, (xxvii) C _{3- 5} alkenoyl group, (xxviii) C _6-10 aryl-carbonyloxy group, (xxix) C _2-6 alkanoyloxy group, (xxx) C _3-5 alkenoyloxy group, (xxxi) C _1-4 alkyl, phenyl A carbamoyl group or a cyclic aminocarbonyl group optionally substituted with one or two substituents selected from C _1-7 acyl and C _1-4 alkoxy-phenyl, (xxxii) C _1-4 alkyl and A thiocarbamoyl group optionally substituted with 1 or 2 substituents selected from phenyl, (xxxiii) C _1-4 alkyl and optionally substituted with 1 or 2 substituents selected from phenyl Good carbamoyloxy group, (xxxiv) C _1-6 alkanoylamino group, (xxxv) C _6-10 aryl-carbonylamino group, (xxxvi) C _1-10 alkoxy-carboxamide group, (xxxvii) C _6-10 aryloxy -Carboxamide group, (xxxviii) C _7-19 aralkyloxy-carboxamide group, (xxxix) C _1-10 alkoxy-carbonyloxy group, (xxxx) C _6-10 aryloxy-carbonyloxy group, (xxxxi) C _{7- 19} aralkyloxy - carbonyloxy group, _{(xxxxii) C 3-10} cycloalkyloxy - carbonyloxy group, _{(xxxxiii) C 1-4} alkyl group and Fe A ureido group which may be substituted with 1 to 3 substituents selected from the above group, (xxxxiv) having 1 to 4 substituents selected from the group consisting of (i) to (xxxxiii) above <1> linear or branched carbon which may have 1 to 4 substituents selected from the group consisting of C _6-10 aryl groups (hereinafter referred to as Substituent Group A). An alkyl group having 1 to 20 carbon atoms, <2> a cycloalkyl group having 3 to 10 carbon atoms, <3> a cycloalkylalkyl group having 4 to 12 carbon atoms, <4> a lower alkenyl group having 3 to 6 carbon atoms, or <5 > Lower alkynyl group having 3 to 6 carbon atoms (wherein the substituent selected from Substituent group A is <1> a linear or branched alkyl group having 1 to 20 carbon atoms, <2> 3 to 3 carbon atoms) 10 cycloalkyl groups, <3> cycloalkylalkyl groups having 4 to 12 carbon atoms, <4> 3 to 6 carbon atoms. Together with a lower alkenyl group or a <5> lower alkynyl group having 3 to 6 carbon atoms, an indanyl group optionally having 1 to 4 substituents selected from the substituent group A, or 1,2, 3,4-tetrahydronaphthyl group may be formed),
(2) a halogen atom, a C _1-4 alkyl group, a C _1-4 alkoxy group, a C _1-4 alkoxy-carbonyl group, a carboxyl group, a nitro group, a cyano group, a hydroxyl group, an alkanoylamino group having 1 to 4 carbon atoms, A cycloalkyl group having 3 to 6 carbon atoms, an aryl group having 6 to 10 carbon atoms, a halogeno C _1-4 alkyl group, a halogeno C _1-4 alkoxy group, a C _1-4 alkylthio group, a C _1-4 alkylsulfonyl group, C _1-4 alkanoyl group, 5-membered aromatic heterocyclic group, carbamoyl group, C _1-4 alkyl-carbamoyl group, C _1-4 alkoxy-carbonyl-C _1-4 alkyl-carbamoyl group and 1,3-diacyl An aromatic hydrocarbon group having 6 to 14 carbon atoms which may have 1 to 5 substituents selected from the group consisting of guanidino-C _1-4 alkyl group,
(3) a nitrogen atom (which may be oxidized) which may have 1 to 3 substituents selected from the group consisting of C _1-4 alkyl, hydroxy, oxo and C _1-4 alkoxy , A 5- to 8-membered cyclic group containing 1 to 4 heteroatoms selected from an oxygen atom and a sulfur atom, or a condensed ring group thereof,
(4) Formula: —OR ¹ (wherein R ¹ may have 1 to 4 substituents selected from (i) a hydrogen atom or (ii) substituent group A) <1> linear Or a branched alkyl group having 1 to 20 carbon atoms, <2> a cycloalkyl group having 3 to 10 carbon atoms, <3> a cycloalkylalkyl group having 4 to 12 carbon atoms, <4> having 3 to 6 carbon atoms. A lower alkenyl group or a <5> lower alkynyl group having 3 to 6 carbon atoms (wherein the substituent selected from the substituent group A is <1> a linear or branched alkyl group having 1 to 20 carbon atoms, <2> a cycloalkyl group having 3 to 10 carbon atoms, <3> a cycloalkylalkyl group having 4 to 12 carbon atoms, <4> a lower alkenyl group having 3 to 6 carbon atoms, or <5> a lower alkynyl group having 3 to 6 carbon atoms. Together with the group, it may have 1 to 4 substituents selected from the substituent group A; A dannyl group or a 1,2,3,4-tetrahydronaphthyl group may be formed), or a group represented by formula (5):

(In the formula, R ^1b may have 1 to 4 substituents selected from (i) a hydrogen atom or (ii) substituent group A <1> linear or branched carbon number 1) ˜20 alkyl group, <2> a cycloalkyl group having 3 to 10 carbon atoms, <3> a cycloalkylalkyl group having 4 to 12 carbon atoms, <4> a lower alkenyl group having 3 to 6 carbon atoms, or <5> carbon. A lower alkynyl group having a number of 3 to 6 (wherein the substituent selected from the substituent group A is <1> a linear or branched alkyl group having 1 to 20 carbon atoms, <2> a group having 3 to 10 carbon atoms) Substituted with a cycloalkyl group, <3> a cycloalkylalkyl group having 4 to 12 carbon atoms, <4> a lower alkenyl group having 3 to 6 carbon atoms, or <5> a lower alkynyl group having 3 to 6 carbon atoms. An indanyl group optionally having 1 to 4 substituents selected from group A, or , 2,3,4-tetrahydronaphthyl group may be formed),
R ^1c may be the same as or different from R ^1b and may have 1 to 4 substituents selected from (i) a hydrogen atom or (ii) substituent group A. <1> Linear or branched An alkyl group having 1 to 20 carbon atoms, <2> a cycloalkyl group having 3 to 10 carbon atoms, <3> a cycloalkylalkyl group having 4 to 12 carbon atoms, <4> a lower alkenyl group having 3 to 6 carbon atoms, or <5> a lower alkynyl group having 3 to 6 carbon atoms (wherein the substituent selected from the substituent group A is <1> a linear or branched alkyl group having 1 to 20 carbon atoms, <2> carbon number Together with a cycloalkyl group having 3 to 10 carbon atoms, <3> a cycloalkylalkyl group having 4 to 12 carbon atoms, <4> a lower alkenyl group having 3 to 6 carbon atoms, or <5> a lower alkynyl group having 3 to 6 carbon atoms. And may have 1 to 4 substituents selected from the substituent group A The may form a indanyl group or 1,2,3,4-tetrahydronaphthyl group),
R ⁰ is a hydrogen atom, a linear or branched alkyl group having 1 to 20 carbon atoms, a cycloalkyl group having 3 to 10 carbon atoms, a cycloalkylalkyl group having 4 to 12 carbon atoms, or a lower group having 3 to 6 carbon atoms. An alkenyl group or a lower alkynyl group having 3 to 6 carbon atoms,
Or R and R ⁰ together join the bond,
Ring A ¹ may have (1) 1 to 4 substituents selected from Substituent Group A <1> linear or branched alkyl group having 1 to 20 carbon atoms, <2> A cycloalkyl group having 3 to 10 carbon atoms, <3> a cycloalkylalkyl group having 4 to 12 carbon atoms, <4> a lower alkenyl group having 3 to 6 carbon atoms, or <5> a lower alkynyl group having 3 to 6 carbon atoms ( Here, the substituent selected from the substituent group A is <1> a linear or branched alkyl group having 1 to 20 carbon atoms, <2> a cycloalkyl group having 3 to 10 carbon atoms, and <3> carbon number. 1 to 4 selected from the substituent group A together with a 4 to 12 cycloalkylalkyl group, <4> a lower alkenyl group having 3 to 6 carbon atoms, or <5> a lower alkynyl group having 3 to 6 carbon atoms. Indanyl group or 1,2,3,4-tetra which may have one substituent A hydronaphthyl group may be formed),
(2) a halogen atom, a C _1-4 alkyl group, a C _1-4 alkoxy group, a C _1-4 alkoxy-carbonyl group, a carboxyl group, a nitro group, a cyano group, a hydroxyl group, an alkanoylamino group having 1 to 4 carbon atoms, A cycloalkyl group having 3 to 6 carbon atoms, an aryl group having 6 to 10 carbon atoms, a halogeno C _1-4 alkyl group, a halogeno C _1-4 alkoxy group, a C _1-4 alkylthio group, a C _1-4 alkylsulfonyl group, C _1-4 alkanoyl group, 5-membered aromatic heterocyclic group, carbamoyl group, C _1-4 alkyl-carbamoyl group, C _1-4 alkoxy-carbonyl-C _1-4 alkyl-carbamoyl group and 1,3-diacyl An aromatic hydrocarbon group having 6 to 14 carbon atoms which may have 1 to 5 substituents selected from the group consisting of guanidino-C _1-4 alkyl group,
(3) substituted with 1 to 4 substituents selected from a group represented by the formula: —OR ¹ (wherein R ¹ is as defined above), or (4) a halogen atom. A good cycloalkene,
Ar is a halogen atom, a C _1-4 alkyl group, a C _1-4 alkoxy group, a C _1-4 alkoxycarbonyl group, a carboxyl group, a nitro group, a cyano group, a hydroxyl group, an alkanoylamino group having 1 to 4 carbon atoms, or a carbon number. A cycloalkyl group having 3 to 6 carbon atoms, an aryl group having 6 to 10 carbon atoms, a halogeno C _1-4 alkyl group, a halogeno C _1-4 alkoxy group, a C _1-4 alkylthio group, a C _1-4 alkylsulfonyl group, C _{1 -4} alkanoyl group, 5-membered aromatic heterocyclic group, carbamoyl group, _C1-4 alkyl-carbamoyl group, _C1-4 alkoxy-carbonyl- _C1-4 alkyl-carbamoyl group and 1,3-diacylguanidino- C _1-4 above showing 1-5 have a substituent good 6 to 14 carbon atoms an aromatic hydrocarbon group selected from the group consisting of alkyl group [ ] Composition.

[35] The compound represented by formula (I) is:
(I) Formula:

[Wherein, R represents an aliphatic hydrocarbon group which may have a substituent, an aromatic hydrocarbon group which may have a substituent, a heterocyclic group which may have a substituent, a formula : -OR ¹ (wherein R ¹ represents a hydrogen atom or an aliphatic hydrocarbon group which may have a substituent) or a group represented by the formula:

(Wherein R ^1b represents a hydrogen atom or an aliphatic hydrocarbon group which may have a substituent, and R ^1c is the same as or different from R ^1b and represents an aliphatic hydrocarbon group which may have a hydrogen atom or a substituent. R ⁰ represents a hydrogen atom or an aliphatic hydrocarbon group, or R and R ⁰ together represent a bond, and ring A ² represents (1) substitution. An aliphatic hydrocarbon group which may have a group, (2) an aromatic hydrocarbon group which may have a substituent, and (3) a formula: —OR ¹ (wherein R ¹ is as defined above) And (4) a cycloalkene substituted with 1 to 4 substituents selected from halogen atoms, Ar represents an aromatic hydrocarbon group which may have a substituent. The formula:

The group represented by the formula:

Or

N represents an integer of 1 to 4. Or a compound represented by formula (ii):

[Wherein, R ^a is an aliphatic hydrocarbon group which may have a substituent, an aromatic hydrocarbon group which may have a substituent, a heterocyclic group which may have a substituent, A group represented by the formula: —OR ^1a (wherein R ^1a represents a hydrogen atom or an aliphatic hydrocarbon group which may have a substituent) or a formula:

Wherein R ^1a is as defined above, and R ^1b is the same as or different from R ^1a and represents a hydrogen atom or an aliphatic hydrocarbon group which may have a substituent. R ^0a represents a hydrogen atom or an aliphatic hydrocarbon group, or R ^a and R ^0a together form a bond, and Ar ^a represents an optionally substituted aromatic hydrocarbon group. :

The group represented by the formula:

Or

N represents an integer of 1 to 4. ] The composition of said [3] description which is a compound represented by this.

  [36] The compound represented by the formula (Iaa) is represented by the formula:

[Wherein each symbol is as defined in [35] above], the composition described in [35] above.

[37] Ring A ² is cycloalkene substituted with lower alkyl, phenyl or halogen, R ¹ is a lower alkyl group, Ar is a phenyl group which may have a substituent, and n is 2 [35] The composition according to [35] above.

  [38] The compound represented by the formula (Ie) is represented by the formula:

[Wherein, R represents an aliphatic hydrocarbon group which may have a substituent, an aromatic hydrocarbon group which may have a substituent, a heterocyclic group which may have a substituent, a formula : -OR ¹ (wherein R ¹ represents a hydrogen atom or an aliphatic hydrocarbon group which may have a substituent) or a group represented by the formula:

(Wherein R ^1b represents a hydrogen atom or an aliphatic hydrocarbon group which may have a substituent, and R ^1c is the same as or different from R ^1b and represents an aliphatic hydrocarbon group which may have a hydrogen atom or a substituent. R ⁰ represents a hydrogen atom or an aliphatic hydrocarbon group, or R and R ⁰ together form a bond, and Ar has a substituent. An aromatic hydrocarbon group that may be represented by the formula:

The group represented by the formula:

Or

N represents an integer of 1 to 4. However, when n is 1 or 2, (i) R ¹ is a hydrogen atom or an ethyl group, R ⁰ is a methyl group, and Ar is a phenyl group, or (ii) R and R ⁰ are combined. When a bond is shown and Ar is a phenyl group, 2-methylphenyl group, 4-bromophenyl group, 4-methoxyphenyl group or 2,6-dimethylphenyl group, the formula:

The group represented by the formula:

It is group represented by these. ] The composition of said [35] description which is a compound represented by this.

  [39] The compound represented by the formula (Ia) is represented by the formula:

[Wherein R ² represents a hydrogen atom or an aliphatic hydrocarbon group, R ¹ , Ar, n and the formula:

Is represented by the same meaning as described in [38] above. However, when n is 1 or 2, Ar is a phenyl group, R ¹ is a hydrogen atom or an ethyl group, and R ² is a methyl group, the formula:

The group represented by the formula:

It is group represented by these. ] The composition of said [38] description which is a compound represented by this.

[40] The composition of the above-mentioned [39], wherein R ¹ is a lower alkyl group which may have a substituent.

[41] The composition of the above-mentioned [39], wherein R ¹ is an ethyl group.

[42] The composition of the above-mentioned [39], wherein R ² is a hydrogen atom or a lower alkyl group.

[43] The composition of the above-mentioned [39], wherein R ² is a hydrogen atom.

  [44] The composition of the above-mentioned [39], wherein Ar is a phenyl group which may have a substituent.

  [45] The composition described in [39] above, wherein Ar is a phenyl group substituted with halogen or / and lower alkyl.

  [46] Ar is the formula:

[Wherein, R ⁴ and R ⁵ are the same or different and each represents a halogen atom or a lower alkyl group, and n represents an integer of 0 to 2. ] The composition of said [39] description which is group represented by these.

  [47] The composition of the above-mentioned [39], wherein the halogen atom is a fluorine atom or a chlorine atom.

  [48] Formula:

A group represented by the formula:

[Wherein n is as defined above in [39]. ] The composition of said [39] description which is group represented by these.

  [49] The composition of the above-mentioned [39], wherein n is 1 to 3.

[50] R ¹ is a lower alkyl group which may have a substituent, R ² is a hydrogen atom or a lower alkyl group, Ar is a phenyl group which may have a substituent, and n The composition of the above-mentioned [39], wherein is 1, 2 or 3.

[51] The above [39], wherein R ¹ is an optionally substituted lower alkyl group, R ² is a hydrogen atom, Ar is a phenyl group substituted with a halogen atom, and n is 2. ] The composition as described.

  [52] The compound represented by the formula (Ia) is represented by the formula:

[Wherein Ar and n are as defined in the above [38],] a composition represented by the above [38].

  [53] The composition of the above-mentioned [52], wherein Ar is a phenyl group which may have a substituent, and n is 2.

  [54] The compound represented by the formula (Ia) is represented by the formula:

[Wherein R ¹ , R ² and Ar have the same meanings as described in [39] above,

The group represented by the formula:

Or

The group represented by these is shown. However, when Ar is a phenyl group, R ¹ is a hydrogen atom or an ethyl group, and R ² is a methyl group, the formula:

The group represented by the formula:

It is group represented by these. ] The composition of said [38] description which is a compound represented by this.

  [55] The compound represented by the formula (Ie) is represented by the formula:

[Wherein R ^2a represents a hydrogen atom or an aliphatic hydrocarbon group, R ^1a , Ar ^a , n and the formula:

Is represented by the same meaning as described in [35] above. ] The composition of said [35] description which is a compound represented by this.

  [56] The compound represented by the formula (Ie) is represented by the formula:

[Wherein, R ^1a , R ^2a and Ar ^a have the same meaning as described in the above [55],

The group represented by the formula:

Or

The group represented by these is shown. ] The composition of said [35] description which is a compound represented by this.

  [57] The composition of the above-mentioned [8], wherein the oil component is selected from the group consisting of vegetable oil, partially hydrogenated oil of vegetable oil, monoacid group glyceride, mixed acid group glyceride and medium chain fatty acid glycerin ester.

  [58] The above [8], wherein the vegetable oil is selected from the group consisting of soybean oil, cottonseed oil, rapeseed oil, peanut oil, safflower oil, sesame oil, rice bran oil, corn germ oil, sunflower oil, poppy oil and olive oil Composition.

  [59] The composition of the above-mentioned [8], wherein the emulsifier is a phospholipid or a nonionic surfactant.

  [60] The phospholipid is egg yolk lecithin, soybean lecithin, hydrogenated products thereof, phosphatidylcholine, phosphatidylethanolamines, phosphatidic acid, phosphatidylserine, phosphatidylinositol or phosphatidyl. The composition according to [8] above, which is glycerol.

  [61] The composition described in [8] above, wherein the emulsifier further contains an anionic phospholipid in an amount of about 0.0001 to about 5% (W / V) based on the composition.

  [62] The composition of the above-mentioned [61], wherein the anionic phospholipid is dimyristoylphosphatidylglycerol.

  [63] The composition of the above-mentioned [8], wherein the ratio of the emulsifier to the oil component is about 0.1 to about 150% by weight.

  Since the pH of the emulsified composition of the present invention is adjusted to about 3.7 to about 5.5 by blending a buffering agent, even after sterilization with an autoclave or the like or after storage for a long period of time, The pH of the emulsified composition and the average particle diameter of the dispersed phase particles hardly change and are stable. Therefore, the emulsified composition of the present invention and the compound which is the main component of the emulsified composition or a salt thereof or a prodrug thereof have excellent stability. Further, even after the emulsion composition of the present invention is sterilized by an autoclave or the like and stored for a long period of time, no visible oil droplets are observed, that is, the dispersed phase particles and the dispersed phase particles are dispersed. The water is stable without phase separation.

  In addition, since the emulsion composition of the present invention can be adjusted to a pH of about 3.7 to about 5.5 by adding a buffering agent to form a stable emulsion composition, An optimum pH can be selected according to other conditions such as stability. Therefore, even when there are other conditions that can be overcome by adjusting the pH in the range of about 3.7 to about 5.5, such as when affecting the stability of the emulsified composition, select the pH adjustment. Thus, an emulsified composition suitable for various conditions can be obtained.

  Furthermore, the emulsified composition of the present invention exhibits a long-term stability of 24 months, which is over 18 months of the typical use period for emulsion formulations.

(Detailed description of the invention)
Hereinafter, embodiments of the present invention will be described.
The compound used in the emulsified composition of the present invention is a compound that is stable in the acidic region described above. Specifically, the compound represented by formula (I) or formula (II), a salt thereof, a prodrug thereof, or the like It is.

(A) In the present specification for the compound of formula (I) , R represents an aliphatic hydrocarbon group which may have a substituent, an aromatic hydrocarbon group which may have a substituent, and a substituent. A heterocyclic group which may have, a group represented by the formula: —OR ¹ (wherein R ¹ represents a hydrogen atom or an aliphatic hydrocarbon group which may have a substituent), or formula:

(In the formula, R ^1b is a hydrogen atom or an aliphatic hydrocarbon group which may have a substituent, and R ^1c is the same as or different from R ^1b and may have a hydrogen atom or a substituent. An aliphatic hydrocarbon group.) Or a group formed together with R ⁰ to form a bond, in particular, the formula: —OR ¹ [wherein R ¹ is as defined above] . ] Which shows group represented by this is preferable.
R ^a is an aliphatic hydrocarbon group which may have a substituent, an aromatic hydrocarbon group which may have a substituent, a heterocyclic group which may have a substituent, a formula: A group represented by —OR ^1a (wherein R ^1a represents a hydrogen atom or an aliphatic hydrocarbon group which may have a substituent), or a group represented by the formula:

(Wherein R ^1a is as defined above, and R ^1b is the same as or different from R ^1a and represents a hydrogen atom or an aliphatic hydrocarbon group which may have a substituent). It shows that a bond is formed together with the group or R ^0a, and in particular, the formula: —OR ^1a [R ^1a is as defined above. ] Which shows group represented by this is preferable.
When R and R ⁰ together represent a bond, the compound represented by the formula (Iaa) has the formula:

[Wherein each symbol is as defined above. Specifically, the formula:

[Wherein each symbol is as defined above. Or

[Wherein each symbol is as defined above. ].
When R and R ⁰ together represent a bond, the compound represented by formula (Ia) has the formula:

[Wherein each symbol is as defined above. Specifically, the formula:

[Wherein each symbol is as defined above. Or

[Wherein each symbol is as defined above. ].
When R ^a and R ^0a together represent a bond, the compound represented by formula (Ie) has the formula:

[Wherein each symbol is as defined above. Specifically, the formula:

[Wherein each symbol is as defined above. Or

[Wherein each symbol is as defined above. ].
R is the formula: —OR ¹ [wherein R ¹ is as defined above. ], The compound represented by the formula (Iaa) is represented by the formula:

[Wherein each symbol is as defined above. Specifically, the formula:

[Wherein each symbol is as defined above. Or

[Wherein each symbol is as defined above. ].
R is the formula: —OR ¹ [wherein R ¹ is as defined above. ], The compound represented by the formula (Ia) is represented by the formula:

[Wherein each symbol is as defined above. Specifically, the formula:

[Wherein each symbol is as defined above. Or

[Wherein each symbol is as defined above. ].
R ^a is represented by the formula: —OR ^1a [wherein R ^1a is as defined above. ] Is a group represented by the formula (Ie):

[Wherein each symbol is as defined above. Specifically, the formula:

[Wherein each symbol is as defined above. Or

[Wherein each symbol is as defined above. ].
The compound represented by the formula (Iaa) is preferably a compound represented by the formula (Icc) or the formula (Inn), and the compound represented by the formula (Ia) is represented by the formula (Ic) or the formula (In). The compound represented by the formula (Ie) is preferable, and the compound represented by the formula (Ik) or the formula (Ip) is preferable.
Similarly, the compound represented by the formula (Id) has the formula:

[Wherein each symbol has the same meaning as described above. ] Or the formula:

[Wherein each symbol has the same meaning as described above. The compound represented by the formula (Ig) is represented by the formula:

[Wherein each symbol has the same meaning as described above. ] Or the formula:

[Wherein each symbol has the same meaning as described above. ].
The compound represented by the formula (Id) is preferably a compound represented by the formula (Ir), and the compound represented by the formula (Ig) is preferably a compound represented by the formula (It).

In the compound represented by the formula (Ia), n is 1 or 2, (i) when R ¹ is a hydrogen atom or an ethyl group, R ⁰ is a methyl group, and Ar is a phenyl group, or (ii) When R and R ⁰ together represent a bond, and Ar is a phenyl group, a 2-methylphenyl group, a 4-bromophenyl group, a 4-methoxyphenyl group, or a 2,6-dimethylphenyl group, the formula :

The group represented by the formula:

It is group represented by these. Further, n is 1 to 4, (i) R ¹ is a hydrogen atom or a lower alkyl group that may have a substituent, R ⁰ is a lower alkyl group that may have a substituent, and Ar Is a phenyl group which may have a substituent, or (ii) R and R ⁰ together represent a bond, and Ar is a phenyl group which may have a substituent. When the formula:

The group represented by the formula:

The group represented by these may be sufficient.
In the compound represented by the formula (Ib), when n is 1 or 2, R ¹ is a hydrogen atom or an ethyl group, R ⁰ is a methyl group, and Ar is a phenyl group, the formula:

The group represented by the formula:

It is group represented by these. Further, n is 1 to 4, R ¹ is a hydrogen atom or a lower alkyl group that may have a substituent, R ⁰ is a lower alkyl group that may have a substituent, and Ar is a substituent. When it is a phenyl group optionally having the formula:

The group represented by the formula:

The group represented by these may be sufficient.
“Aliphatic hydrocarbon group” of “ ^optionally substituted aliphatic hydrocarbon group” represented by R, R ^a , R ¹ , R ^1a , R ^1b , R ^1c , R ⁰ , R ^0a As the “aliphatic hydrocarbon group” represented by R ² and R ^2a , for example, an alkyl group, a cycloalkyl group, a cycloalkylalkyl group, an alkenyl group, an alkynyl group and the like are preferable.

  Examples of the alkyl group include linear or branched alkyl groups having 1 to 20 carbon atoms (eg, methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, sec- A butyl group, a tert-butyl group, a pentyl group, a hexyl group, a heptyl group, an octyl group, a nonyl group, a decyl group, a dodecyl group, and the like, among others, for example, a lower alkyl group having 1 to 6 carbon atoms (e.g., Methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, sec-butyl group, tert-butyl group and the like are preferred.

  As the cycloalkyl group, for example, a cycloalkyl group having 3 to 10 carbon atoms (eg, cyclopropyl group, cyclobutyl group, cyclopentyl group, cyclohexyl group, cycloheptyl group, cyclooctyl group, etc.) is preferable. And a cycloalkyl group having 3 to 6 carbon atoms (eg, cyclopropyl group, cyclobutyl group, cyclopentyl group, cyclohexyl group, etc.) are preferred.

  As the cycloalkylalkyl group, for example, a cycloalkylalkyl group having 4 to 12 carbon atoms (eg, cyclopropylmethyl group, cyclopentylmethyl group, cyclohexylmethyl group, cycloheptylmethyl group, etc.) is preferable. A cycloalkylalkyl group having 4 to 8 carbon atoms (in particular, 4 to 7 carbon atoms) (eg, cyclopropylmethyl group, cyclopentylmethyl group, cyclohexylmethyl group, etc.) and the like are preferable.

  As the alkenyl group, for example, a lower alkenyl group having 3 to 6 carbon atoms (eg, propenyl group, butenyl group, pentenyl group, etc.) and the like are preferable, and in particular, for example, a lower alkenyl group having 3 or 4 carbon atoms (eg, Propenyl group, butenyl group, etc.) are preferred.

  The alkynyl group is preferably, for example, a lower alkynyl group having 3 to 6 carbon atoms (eg, propynyl group, butynyl group, pentynyl group, etc.), and particularly, for example, a lower alkynyl group having 3 or 4 carbon atoms (eg, propynyl) Group, butynyl group, etc.) are preferred.

As the “substituent” of the “aliphatic hydrocarbon group optionally having substituent (s)”, for example, a heterocyclic group, an oxo group, a hydroxyl group, a C _1-6 alkoxy group, C _3-10 (among others) C _3-6 ) cycloalkyloxy group, C _6-10 aryloxy group, C _7-19 (among others C _7-12 ) aralkyloxy group, heterocyclic oxy group, C _1-6 alkylthio group (the sulfur atom is C _3-10 (especially C _3-6 ) cycloalkylthio group (the sulfur atom may be oxidized), C _6-10 arylthio group (the sulfur atom is an oxide) C _7-19 (especially C _7-12 ) aralkylthio group (the sulfur atom may be oxidized), heterocyclic thio group, heterocyclic sulfinyl group, heterocyclic sulfonyl Base A nitro group, a halogen atom, a cyano group, a carboxyl _{group, C 1-10} (among others _{C 1-6)} alkoxy - carbonyl _{group, C 3-6} cycloalkyloxy - carbonyl _{group, C 6-10} aryloxy - carbonyl group, C _7-19 (among others _{C 7-12)} aralkyloxy - carbonyl group, a heterocyclic oxycarbonyl _{group, C 6-10} aryl - carbonyl _{group, C 1-6} alkanoyl _{group, C 3-5} alkenoyl _{group, C 6- 10} aryl-carbonyloxy group, C _2-6 alkanoyloxy group, C _3-5 alkenoyloxy group, optionally substituted carbamoyl group, optionally substituted thiocarbamoyl group, substituted A carbamoyloxy group optionally having a group, a C _1-6 alkanoylamino group, a C _6-10 aryl-carbonyl group Mino group, C _1-10 (among others C _1-6 ) alkoxy-carboxamide group, C _6-10 aryloxy-carboxamide group, C _7-19 (among others C _7-12 ) aralkyloxy-carboxamide group, C _{1 -10} (especially C _1-6 ) alkoxy-carbonyloxy group, C _6-10 aryloxy-carbonyloxy group, C _7-19 (particularly C _7-12 ) aralkyloxy-carbonyloxy group, C _3-10 (Especially C _3-6 ) cycloalkyloxy-carbonyloxy group, ureido group which may have a substituent, C _6-10 aryl group which may have a substituent, and the like are used.

  These substituents are substituted at substitutable sites of the “aliphatic hydrocarbon group”. The number of substituents is not limited to one, and there may be a plurality (2 to 4) of the same or different. Good.

Examples of the “C _1-6 alkoxy group” include methoxy group, ethoxy group, n-propoxy group, isopropoxy group, n-butoxy group, tert-butoxy group, n-pentyloxy group, n-hexyloxy group and the like. However, examples of the “C _3-10 cycloalkyloxy group” include a cyclopropyloxy group and a cyclohexyloxy group, and examples of the “C _6-10 aryloxy group” include a phenoxy group and a naphthyloxy group. , “C _7-19 aralkyloxy group” includes, for example, benzyloxy group, 1-phenylethyloxy group, 2-phenylethyloxy group, benzhydryloxy group, 1-naphthylmethyloxy group, etc. _1-6 the alkylthio group (the sulfur atom may be oxidized) ", for example, a methylthio group, e Thio group, n- propylthio group, n- butylthio group, methylsulfinyl group, methylsulfonyl group, the "C _3-10 cycloalkylthio group (the sulfur atom may be oxidized)", for example, A cyclopropylthio group, a cyclohexylthio group, a cyclopentylsulfinyl group, a cyclohexylsulfonyl group and the like, as the “C _6-10 arylthio group (the sulfur atom may be oxidized)”, for example, a phenylthio group, a naphthylthio group , Phenylsulfinyl group, phenylsulfonyl group, etc., as "C _7-19 aralkylthio group (the sulfur atom may be oxidized)", for example, benzylthio group, phenylethylthio group, benzhydrylthio group , Benzylsulfinyl group, benzylsulfonyl Etc., as the "halogen atom" include fluorine atom, a chlorine atom, a bromine atom, an iodine atom, - as the "C _1-10 alkoxy-carbonyl group", for example, a methoxycarbonyl group, an ethoxycarbonyl radical, n -Propoxycarbonyl group, isopropoxycarbonyl group, n-butoxycarbonyl group, isobutoxycarbonyl group, tert-butoxycarbonyl group and the like are exemplified by “C _3-6 cycloalkyloxy-carbonyl group” such as cyclopropyloxycarbonyl Group, cyclopentyloxycarbonyl group, cyclohexyloxycarbonyl group, norbornyloxycarbonyl group, etc., and “C _6-10 aryloxy-carbonyl group” includes, for example, phenoxycarbonyl group, naphthyloxycarbonyl group, etc. _{7- 9} aralkyloxy - carbonyl group ", for example, benzyloxycarbonyl group, benzhydryloxy group, such as 2-phenethyl oxycarbonyl group," C _6-10 aryl - as carbonyl group ", for example, benzoyl group , Naphthoyl group, phenylacetyl group, etc., as “C _1-6 alkanoyl group”, for example, formyl group, acetyl group, propionyl group, butyryl group, valeryl group, pivaloyl group and the like are referred to as “C _3-5 alkenoyl group”. the "example, an acryloyl group, a crotonoyl group," C _6-10 aryl - the carbonyloxy group ", for example, benzoyloxy group, naphthoyloxy group, phenylacetoxy group," C _2-6 Examples of the “alkanoyloxy group” include an acetoxy group , Propionyloxy group, butyryloxy group, valeryloxy group, pivaloyloxy group, etc. As the “C _3-5 alkenoyloxy group”, for example, acryloyloxy group, crotonoyloxy group and the like are used.

Examples of the “optionally substituted carbamoyl group” include C _1-4 alkyl (eg, methyl, ethyl, etc.), phenyl, C _1-7 acyl (eg, acetyl, propionyl, benzoyl, etc.), A carbamoyl group or a cyclic aminocarbonyl group which may be substituted with one or two substituents selected from C _1-4 alkoxy-phenyl (eg, methoxyphenyl etc.) and the like are used. For example, carbamoyl group, N-methylcarbamoyl group, N-ethylcarbamoyl group, N, N-dimethylcarbamoyl group, N, N-diethylcarbamoyl group, N-phenylcarbamoyl group, N-acetylcarbamoyl group, N-benzoylcarbamoyl Group, N- (p-methoxyphenyl) carbamoyl group, 1-pyrrolidinylcarbonyl group, Piperidino group, 1-piperazinylcarbonyl group, a morpholinocarbonyl group, etc. are used. The “optionally substituted thiocarbamoyl group” is, for example, substituted with 1 or 2 substituents selected from C _1-4 alkyl (eg, methyl, ethyl, etc.), phenyl and the like. An optional thiocarbamoyl group is used, and specifically, for example, a thiocarbamoyl group, an N-methylthiocarbamoyl group, an N-phenylthiocarbamoyl group, or the like is used. The “optionally substituted carbamoyloxy group” is, for example, substituted with 1 or 2 substituents selected from C _1-4 alkyl (eg, methyl, ethyl, etc.), phenyl and the like. Carbamoyloxy group which may be used, specifically, for example, carbamoyloxy group, N-methylcarbamoyloxy group, N, N-dimethylcarbamoyloxy group, N-ethylcarbamoyloxy group, N-phenylcarbamoyloxy group Etc. are used.

Examples of the “C _1-6 alkanoylamino group” include an acetamide group, a propionamide group, a butyroamide group, a valeramide group, a pivalamide group, and the like, and examples of the “C _6-10 aryl-carbonylamino group” include a benzamide group. , naphthamide group, a phthalimide group, - a _{"C 1-10} alkoxy-carboxamide group", for example, methoxy carboxamide _(CH 3 OCONH-) group, ethoxy carboxamide group, such as tert- butoxy carboxamide group, _{"C 6-} Examples of the “ ₁₀ aryloxy-carboxamide group” include a phenoxycarboxamide (C ₆ H ₅ OCONH—) group, and the “C _7-19 aralkyloxy-carboxamide group” includes, for example, a benzyloxycarboxamide (C ₆ H ₅ CH OCONH-) group, etc. benzhydryloxy carboxamide group, - a "C _1-10 alkoxy-carbonyloxy group", for example, a methoxycarbonyloxy group, an ethoxycarbonyloxy group, n- propoxycarbonyl group, isopropoxycarbonyl An oxy group, an n-butoxycarbonyloxy group, a tert-butoxycarbonyloxy group, an n-pentyloxycarbonyloxy group, an n-hexyloxycarbonyloxy group, and the like, as the “C _6-10 aryloxy-carbonyloxy group” For example, phenoxycarbonyl group, etc. naphthyloxycarbonyl group is - as the "C _7-19 aralkyloxy-carbonyloxy group", for example, benzyloxycarbonyl group, 1-phenylethyl oxycarboxin Aryloxy group, 2-phenylethyl oxycarbonyl group, etc. benzhydryloxy carbonyl group is - as the "C _3-10 cycloalkyloxy-carbonyloxy group", for example, cyclopropyloxycarbonyl group, cyclohexyloxycarbonyl An oxy group or the like is used.

Examples of the “ureido group optionally having substituent (s)” include 1 to 3 (among others 1) selected from a C _1-4 alkyl group (eg, methyl group, ethyl group, etc.), a phenyl group and the like. Or a ureido group optionally substituted with two substituents, for example, ureido group, 1-methylureido group, 3-methylureido group, 3,3-dimethylureido group, 1,3-dimethylureido Group, 3-phenylureido group and the like are used.

  As the “substituent” of the “optionally substituted aliphatic hydrocarbon group”, a heterocyclic group, heterocyclic oxy group, heterocyclic thio group, heterocyclic sulfinyl group, heterocyclic sulfonyl group or heterocyclic oxy When a carbonyl group is used, the heterocyclic group represents a group capable of removing one hydrogen atom bonded to the heterocyclic ring, for example, a nitrogen atom (which may be oxidized), an oxygen atom, a sulfur atom A 5- to 8-membered ring (in particular, 5 to 6-membered ring) group containing 1 to several, preferably 1 to 4 heteroatoms, or a condensed ring group thereof. Examples of such heterocyclic groups include pyrrolyl, pyrazolyl, imidazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, tetrazolyl, furyl, thienyl, oxazolyl, and isoxazolyl. Group, 1,2,3-oxadiazolyl group, 1,2,4-oxadiazolyl group, 1,2,5-oxadiazolyl group, 1,3,4-oxadiazolyl group, thiazolyl group, isothiazolyl group, 1,2,3- Thiadiazolyl group, 1,2,4-thiadiazolyl group, 1,2,5-thiadiazolyl group, 1,3,4-thiadiazolyl group, pyridyl group, pyridazinyl group, pyrimidinyl group, pyrazinyl group, indolyl group, pyranyl group, thiopyranyl group , Dioxynyl group, dioxolyl group, quinolyl group, pyrido [2,3-d] pyrimidyl group, 1, -, 1,6-, 1,7-, 1,8-, 2,6- or 2,7-naphthyridyl group, thieno [2,3-d] pyridyl group, benzopyranyl group, tetrahydrofuryl group, tetrahydropyranyl Group, dioxolanyl group, dioxanyl group and the like are used.

These heterocyclic groups are represented by 1 to 3 substituents selected from C _1-4 alkyl (eg, methyl, ethyl, etc.), hydroxy, oxo, C _1-4 alkoxy (eg, methoxy, ethoxy, etc.), etc. It may be substituted at a substitutable site.

As the “C _6-10 aryl group” of the “ _optionally substituted C _6-10 aryl group”, for example, a phenyl group, a naphthyl group, and the like are used. The C _6-10 aryl group is the “substituent” of the “aliphatic hydrocarbon group _optionally having substituent (s)” (excluding the C _6-10 aryl group _optionally having substituent (s)). The substitutable portion may be substituted with a substituent selected from Those substituents are substituted at substitutable positions of the C _6-10 aryl group, and the substituent is not limited to one, and there may be a plurality (2 to 4) of the same or different. Good.

  Further, the “aliphatic hydrocarbon group optionally having substituent (s)” may form a condensed ring group in which the substituent may be substituted together with the aliphatic hydrocarbon group, As such a condensed ring group, indanyl group, 1,2,3,4-tetrahydronaphthyl group and the like are used. In this fused ring group, a substitutable site may be substituted with a substituent selected from “substituent” of the “aliphatic hydrocarbon group optionally having substituent (s)”. Those substituents are substituted at substitutable sites of the fused ring group, and the number of substituents is not limited to one, and there may be a plurality (2 to 4) of the same or different.

Examples of R, R ^a , R ¹ , R ^1a , R ^1b , and R ^1c include a lower alkyl group having 1 to 6 carbon atoms that may have a substituent (eg, methyl group, ethyl group, n- Propyl group, isopropyl group, n-butyl group, isobutyl group, tert-butoxycarbonylmethyl group, hydroxyethyl group, etc.) are preferably used. Among them, for example, methyl group, ethyl group, n-propyl group, isopropyl group , N-butyl group, isobutyl group and the like are preferably used. In particular, for example, a methyl group, an ethyl group, an n-propyl group and the like are preferable, and an ethyl group and the like are particularly preferable.

Examples of R ² and R ^2a include a hydrogen atom and a lower alkyl group having 1 to 6 carbon atoms (eg, methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, tert-butoxy group). A carbonylmethyl group, a hydroxyethyl group, etc.) are preferably used. In particular, a hydrogen atom, a methyl group and the like are preferably used, and a hydrogen atom and the like are particularly preferably used.

Examples of R ⁰ and R ^0a include a hydrogen atom and a lower alkyl group having 1 to 6 carbon atoms (eg, methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, tert-butoxy group). A carbonylmethyl group, a hydroxyethyl group, etc.) are preferably used, and a hydrogen atom, a methyl group, etc. are particularly preferably used.

The “aromatic hydrocarbon group” in the “optionally substituted aromatic hydrocarbon group” represented by R and R ^a is an aromatic hydrocarbon group having 6 to 14 carbon atoms (eg, phenyl Group, naphthyl group, biphenyl group, anthryl group, indenyl group and the like are preferable, and in particular, an aryl group having 6 to 10 carbon atoms (eg, phenyl group, naphthyl group, etc.) is preferable, and among them, phenyl group and the like are preferable. Is particularly preferred.

Examples of the “substituent” in the “optionally substituted aromatic hydrocarbon group” represented by R and R ^a include, for example, a halogen atom (eg, fluorine, chlorine, bromine, iodine, etc.), lower (C _1-4 ) alkyl group (eg, methyl group, ethyl group, propyl group, butyl group, etc.), lower (C _1-4 ) alkoxy group (eg, methoxy group, ethoxy group, propoxy group, butoxy group, etc.) , Lower (C _1-4 ) alkoxy-carbonyl group (eg, methoxycarbonyl group, ethoxycarbonyl group, propoxycarbonyl group, butoxycarbonyl group, etc.), carboxyl group, nitro group, cyano group, hydroxyl group, acylamino group (eg, acetyl) C1-C4 alkanoylamino groups such as amino group, propionylamino group, butyrylamino group, etc.), C3-C6 cycloalkyl Group (eg, cyclopropyl group, cyclopentyl group, etc.), aryl group having 6 to 10 carbon atoms (eg, phenyl group, naphthyl group, indenyl group, etc.), halogeno lower (C _1-4 ) alkyl group (eg, trifluoro) Methyl group, trifluoroethyl group, etc.), halogeno lower (C _1-4 ) alkoxy group (eg, trifluoromethoxy group, 1,1,2,2-tetrafluoroethoxy group, 2,2,3,3,3) -Pentafluoropropoxy group, etc.), lower ( _C1-4 ) alkylthio group (eg, methylthio group, ethylthio group, propionylthio group, etc.), lower ( _C1-4 ) alkylsulfonyl group (eg, methanesulfonyl group, ethane) Sulfonyl group, propanesulfonyl group, etc.), lower (C _1-4 ) alkanoyl group (eg, formyl group, acetyl group, propionyl group, etc.) 5-membered aromatic heterocyclic group (eg, 1,2,3-triazolyl group, 1,2,4-triazolyl group, tetrazolyl group, thiazolyl group, isothiazolyl group, oxazolyl group, isoxazolyl group, thiadiazolyl group, thienyl group , Furyl group, etc.), carbamoyl group, lower (C _1-4 ) alkyl-carbamoyl group (eg, methylcarbamoyl group, dimethylcarbamoyl group, propionylcarbamoyl group, etc.), lower (C _1-4 ) alkoxy-carbonyl-lower ( C _1-4 ) alkyl-carbamoyl group (eg, butoxycarbonylmethylcarbamoyl group, ethoxycarbonylmethylcarbamoyl group, etc.), 1,3-diacylguanidino-lower (C _1-4 ) alkyl group (eg, 1,3-diacetyl) Guanidinomethyl, 1,3-bis-tert-butoxycarbonyl Anijinomechiru etc.) and the like, preferably a halogen atom (e.g., fluorine atom, chlorine atom, bromine atom, iodine atom), a lower (C _1-4) alkyl group (e.g., methyl group, ethyl group, propyl group, butyl group More preferably, a fluorine atom, a chlorine atom, or a methyl group is used.

  These substituents are substituted at substitutable sites of the aromatic hydrocarbon group, and the number of substituents is preferably 1 to 5, more preferably 1 to 3, and particularly preferably 1 to 2. When two or more substituents are present, these substituents may be the same or different.

The “heterocyclic group” in the “optionally substituted heterocyclic group” represented by R and R ^a is, for example, a nitrogen atom (which may be oxidized), an oxygen atom, a sulfur atom, etc. A 5- to 8-membered ring group (in particular, a 5- to 6-membered ring) group containing 1 to several, preferably 1 to 4 heteroatoms, or a condensed ring group thereof. Examples of such heterocyclic groups include pyrrolyl, pyrazolyl, imidazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, tetrazolyl, furyl, thienyl, oxazolyl, and isoxazolyl. Group, 1,2,3-oxadiazolyl group, 1,2,4-oxadiazolyl group, 1,2,5-oxadiazolyl group, 1,3,4-oxadiazolyl group, thiazolyl group, isothiazolyl group, 1,2,3- Thiadiazolyl group, 1,2,4-thiadiazolyl group, 1,2,5-thiadiazolyl group, 1,3,4-thiadiazolyl group, pyridyl group, pyridazinyl group, pyrimidinyl group, pyrazinyl group, indolyl group, pyranyl group, thiopyranyl group , Dioxynyl group, dioxolyl group, quinolyl group, pyrido [2,3-d] pyrimidyl group, 1, -, 1,6-, 1,7-, 1,8-, 2,6- or 2,7-naphthyridyl group, thieno [2,3-d] pyridyl group, benzopyranyl group, tetrahydrofuryl group, tetrahydropyranyl Group, dioxolanyl group, dioxanyl group and the like are used.

These heterocyclic groups are substituted with 1 to 3 substituents selected from C _1-4 alkyl (eg, methyl, ethyl, etc.), hydroxy, oxo, C _1-4 alkoxy (eg, methoxy, ethoxy, etc.), etc. It may be substituted at a substitutable site.

The “aromatic hydrocarbon group” in the “aromatic hydrocarbon group which may have a substituent” represented by Ar or Ar ^a is an aromatic hydrocarbon group having 6 to 14 carbon atoms (eg, phenyl). Group, naphthyl group, biphenyl group, anthryl group, indenyl group, etc.) are preferable, and in particular, an aryl group having 6 to 10 carbon atoms (eg, phenyl group, naphthyl group, etc.) is preferable. Is particularly preferred.

Ar, as the "substituent" of the "aromatic substituted hydrocarbon group" represented by Ar ^a, for example, a halogen atom (e.g., fluorine, chlorine, bromine, iodine), lower (C _1-4 ) alkyl group (eg, methyl group, ethyl group, propyl group, butyl group, etc.), lower (C _1-4 ) alkoxy group (eg, methoxy group, ethoxy group, propoxy group, butoxy group, etc.) , Lower (C _1-4 ) alkoxycarbonyl group (eg, methoxycarbonyl group, ethoxycarbonyl group, propoxycarbonyl group, butoxycarbonyl group, etc.), carboxyl group, nitro group, cyano group, hydroxyl group, acylamino group (eg, acetylamino) Groups, propionylamino groups, butyrylamino groups and the like, alkanoylamino groups having 1 to 4 carbon atoms, etc., and cycloalkyl groups having 3 to 6 carbon atoms (Eg, cyclopropyl group, cyclopentyl group, etc.), C6-C10 aryl group (eg, phenyl group, naphthyl group, indenyl group, etc.), halogeno lower (C _1-4 ) alkyl group (eg, trifluoromethyl) Group, trifluoroethyl group, etc.), halogeno lower (C _1-4 ) alkoxy group (eg, trifluoromethoxy group, 1,1,2,2-tetrafluoroethoxy group, 2,2,3,3,3- Pentafluoropropoxy group, etc.), lower (C _1-4 ) alkylthio group (eg, methylthio group, ethylthio group, propionylthio group, etc.), lower (C _1-4 ) alkylsulfonyl group (eg, methanesulfonyl group, ethanesulfonyl) Group, propanesulfonyl group, etc.), lower (C _1-4 ) alkanoyl group (eg, formyl group, acetyl group, propionyl group, etc.), 5 Member aromatic heterocyclic group (eg, 1,2,3-triazolyl group, 1,2,4-triazolyl group, tetrazolyl group, thiazolyl group, isothiazolyl group, oxazolyl group, isoxazolyl group, thiadiazolyl group, thienyl group, furyl group) Group), carbamoyl group, lower (C _1-4 ) alkyl-carbamoyl group (eg, methylcarbamoyl group, dimethylcarbamoyl group, propionylcarbamoyl group), lower (C _1-4 ) alkoxy-carbonyl-lower (C _{1 -4} ) alkyl-carbamoyl group (eg, butoxycarbonylmethylcarbamoyl group, ethoxycarbonylmethylcarbamoyl group, etc.), 1,3-diacylguanidino-lower (C _1-4 ) alkyl group (eg, 1,3-diacetylguanidinomethyl) 1,3-bis-tert-butoxycarbonylgua Jinomechiru etc.) and the like, preferably a halogen atom (e.g., fluorine atom, chlorine atom, bromine atom, iodine atom), a lower (C _1-4) alkyl group (e.g., methyl group, ethyl group, propyl group, butyl group More preferably, a fluorine atom, a chlorine atom, or a methyl group is used.

  These substituents are substituted at substitutable sites of the aromatic hydrocarbon group, and the number of substituents is preferably 1 to 5, more preferably 1 to 3, and particularly preferably 1 to 2. When two or more substituents are present, these substituents may be the same or different.

Specific examples of Ar and Ar ^a include, for example, phenyl group, halogenophenyl group, lower (C _1-4 ) alkylphenyl group, lower (C _1-4 ) alkoxyphenyl group, and lower (C _1-4 ) alkoxy. Carbonylphenyl group, carboxylphenyl group, nitrophenyl group, cyanophenyl group, halogeno lower (C _1-4 ) alkylphenyl group, halogeno lower (C _1-4 ) alkoxyphenyl group, lower (C _1-4 ) alkanoylphenyl group A phenyl group substituted with a 5-membered aromatic heterocycle, a lower (C _1-4 ) alkoxy-carbonyl-lower (C _1-4 ) alkyl-carbamoylphenyl group, 1,3-diacylguanidino-lower (C _{1 -4)} alkylphenyl group, halogen and lower _{(C 1-4)} alkyl-substituted phenyl group, a halogen Contact Fine lower (C _1-4) alkoxy-substituted phenyl group carbonyl, halogen and cyano-substituted phenyl group, a halogen and 5-membered aromatic heterocycle-substituted phenyl group, halogen and lower (C _{1- 4} ) A phenyl group substituted with alkoxy-carbonyl-lower (C _1-4 ) alkyl-carbamoyl is used.

As Ar and Ar ^a , a halogenophenyl group, a lower (C _1-4 ) alkylphenyl group, a phenyl group substituted with halogen and lower (C _1-4 ) alkoxycarbonyl, and the like are preferably used.
Ar and Ar ^a are represented by the formula:

[Wherein, R ⁴ and R ⁵ are the same or different and each represents a halogen atom or a lower alkyl group, and n represents an integer of 0 to 2. And more preferably those in which at least one of R ⁴ and R ⁵ is a halogen atom.

The halogen atom represented by R ⁴ and R ⁵ is preferably a fluorine atom or a chlorine atom.

  Examples of the halogenophenyl group include 2,3-difluorophenyl group, 2,3-dichlorophenyl group, 2,4-difluorophenyl group, 2,4-dichlorophenyl group, 2,5-difluorophenyl group, 2,5 -Dichlorophenyl group, 2,6-difluorophenyl group, 2,6-dichlorophenyl group, 3,4-difluorophenyl group, 3,4-dichlorophenyl group, 3,5-difluorophenyl group, 3,5-dichlorophenyl group, 2 -Fluorophenyl group, 2-chlorophenyl group, 3-fluorophenyl group, 3-chlorophenyl group, 4-fluorophenyl group, 4-chlorophenyl group, 2-fluoro-4-chlorophenyl group, 2-chloro-4-fluorophenyl group 4-bromo-2-fluorophenyl group, 2,3,4-trifluorophenyl group 2,4,5-trifluorophenyl group, a 2,4,6-trifluorophenyl is used.

As the lower (C _1-4 ) alkylphenyl group, for example, 2-ethylphenyl group, 2,6-diisopropylphenyl group and the like are preferably used, and as the lower (C _1-4 ) alkoxyphenyl group, for example 4-methoxyphenyl and the like are preferably used.

As the lower (C _1-4 ) alkoxycarbonylphenyl group, for example, 2-ethoxycarbonylphenyl group, 2-methoxycarbonylphenyl group, 4-methoxycarbonylphenyl group and the like are preferably used, and the halogeno lower (C _{1- 4} ) As the alkylphenyl group, for example, 2-trifluoromethylphenyl group is preferably used, and as the halogeno lower (C _1-4 ) alkoxyphenyl group, for example, 2-trifluoromethoxyphenyl group, 4- A (2,2,3,3,3-pentafluoropropoxy) phenyl group or the like is preferably used.

As the lower (C _1-4 ) alkanoylphenyl group, for example, 2-acetylphenyl group is preferably used, and as the phenyl group substituted with the 5-membered aromatic heterocyclic ring, for example, 4- (2H -1,2,3-triazol-2-yl) phenyl group, 4- (2H-tetrazol-2-yl) phenyl group, 4- (1H-tetrazol-1-yl) phenyl group, 4- (1H-1) , 2,3-triazol-1-yl) phenyl group are preferably used, said lower _{(C 1-4)} alkoxy - carbonyl - lower _{(C 1-4)} alkyl - as a carbamoylphenyl group, for example, 4- such as (N- ethoxycarbonyl-methylcarbamoyl) phenyl group are preferably used, the 1,3-diacylguanidino - a lower _{(C 1-4)} alkylphenyl group Is, for example, 4- (1,3-bis -tert- butoxycarbonyl-guanidino) phenyl group are preferably used.

Examples of the phenyl group substituted with the halogen and lower (C _1-4 ) alkyl include, for example, 2-fluoro-4-methylphenyl group, 2-chloro-4-methylphenyl group, 4-fluoro-2-methylphenyl group A phenyl group substituted with the halogen and lower (C _1-4 ) alkoxycarbonyl, for example, a 2-chloro-4-methoxycarbonylphenyl group is preferably used. As the phenyl group substituted with, 2-chloro-4-cyanophenyl group or the like is preferably used, and as the phenyl group substituted with the halogen and a 5-membered aromatic heterocyclic ring, for example, 2-fluoro-4 - (IH-1,2,4-triazol-1-yl) phenyl and the like are preferably used, the halogen and lower (C _-4) alkoxy - carbonyl - lower _{(C 1-4)} - alkyl - as the phenyl group substituted with carbamoyl, for example, 2-chloro-4-(N-tert-butoxycarbonyl-methylcarbamoyl) phenyl group, 2- A chloro-4- (N-ethoxycarbonylmethylcarbamoyl) phenyl group and the like are preferably used.

More specifically, Ar, as the Ar ^a, especially phenyl group, 1 to 3 (particularly 1 to 2) halogen-substituted phenyl group (e.g., 2,3-difluorophenyl group, 2,3 -Dichlorophenyl group, 2,4-difluorophenyl group, 2,4-dichlorophenyl group, 2,5-difluorophenyl group, 2,5-dichlorophenyl group, 2,6-difluorophenyl group, 2,6-dichlorophenyl group, 3 , 4-difluorophenyl group, 3,4-dichlorophenyl group, 3,5-difluorophenyl group, 3,5-dichlorophenyl group, 4-bromo-2-fluorophenyl group, 2-fluorophenyl group, 2-chlorophenyl group, 3-fluorophenyl group, 3-chlorophenyl group, 4-fluorophenyl group, 4-chlorophenyl group, 2-fluoro-4-alkyl Substituted with a halophenyl group, a 2-chloro-4-fluorophenyl group, a 2,3,4-trifluorophenyl group, a 2,4,5-trifluorophenyl group, etc.), halogen and lower (C _1-4 ) alkyl And phenyl groups (eg, 2-chloro-4-methylphenyl group, 4-fluoro-2-methylphenyl group, etc.) are preferred. Among them, a phenyl group substituted with 1 to 3 (especially 1 to 2) halogens (eg, 2,3-dichlorophenyl group, 2,4-difluorophenyl group, 2,4-dichlorophenyl group, 2, 6-dichlorophenyl group, 2-fluorophenyl group, 2-chlorophenyl group, 3-chlorophenyl group, 2-chloro-4-fluorophenyl group, 2,4,5-trifluorophenyl group, etc.), halogen and lower (C _{1 -4} ) A phenyl group substituted with alkyl (eg, 2-chloro-4-methylphenyl group, 4-fluoro-2-methylphenyl group, etc.) and the like are preferable. In particular, 2,4-difluorophenyl group, 2-chlorophenyl group, 2-chloro-4-fluorophenyl group, 2-chloro-4-methylphenyl group and the like are preferable, 2,4-difluorophenyl group, 2-chloro- A 4-fluorophenyl group and the like are preferable.

In the present specification, ring A ¹ is (1) an aliphatic hydrocarbon group which may have a substituent, (2) an aromatic hydrocarbon group which may have a substituent, (3) formula:- A group represented by OR ¹ (wherein R ¹ is as defined above) and (4) a cycloalkene optionally substituted with 1 to 4 substituents selected from a halogen atom. (1) an aliphatic hydrocarbon group which may have a substituent, (2) an aromatic hydrocarbon group which may have a substituent, and (4) 1 to 4 selected from a halogen atom A cycloalkene which may be substituted with a substituent is preferred.

In the present specification, ring A ² is (1) an aliphatic hydrocarbon group which may have a substituent, (2) an aromatic hydrocarbon group which may have a substituent, (3) formula:- A group represented by OR ¹ (wherein R ¹ is as defined above) and (4) a cycloalkene substituted with 1 to 4 substituents selected from a halogen atom, An aliphatic hydrocarbon group which may have a substituent, (2) an aromatic hydrocarbon group which may have a substituent, and (4) 1 to 4 substituents selected from a halogen atom. Substituted cycloalkenes are preferred.

These substituents are substituted on substitutable carbon atoms in the ring A ¹ and ring A ^2, wherein ring A ¹ and ring A ² is substituted by a plurality of substituents, these substituents The type of group may be the same or different. Further, two substituents may be substituted on the same carbon atom, and a plurality of substituents may be substituted on different carbon atoms.

Examples of the “aliphatic hydrocarbon group which may have a substituent” which are the substituents of the ring A ¹ and the ring A ² include, for example, the aforementioned R, R ^a , R ¹ , R ^1a , R ^1b , R ^{The same} “aliphatic hydrocarbon group optionally having substituents” represented by ^1c can be used.

Examples of the “aromatic hydrocarbon group which may have a substituent” which are the substituents of the ring A ¹ and the ring A ² include, for example, the “having a substituent” represented by the aforementioned Ar and Ar ^a. The thing similar to "the aromatic hydrocarbon group which may be used" can be used.

Examples of the substituent for ring A ¹ and ring A ² include 1 or 2 C _1-6 alkyl groups (eg, C _1-4 alkyl groups such as methyl group, tert-butyl group), phenyl group, halogen atom ( For example, fluorine, chlorine, bromine, iodine, etc.) are preferably used.
formula:

[Wherein n is as defined above. The group represented by the formula:

Or

[Wherein n is as defined above. Is a group represented by the formula:

[Wherein n is as defined above. It is preferable that it is group represented by this.
formula:

[Wherein n is as defined above. The group represented by the formula:

Or

[Wherein n is as defined above. Is a group represented by the formula:

[Wherein n is as defined above. It is preferable that it is group represented by this.
Also the formula:

The group represented by the formula:

Or

Is a group represented by the formula:

It is preferable that it is group represented by these.
As an integer of 1-4 represented by n, 1-3 are preferable, and 2 is especially preferable.

  As the compound represented by the formula (Iaa), a compound represented by the formula (Ibb) is preferable, and as the compound represented by the formula (Ia), a compound represented by the formula (Ib) is preferable.

  The compound represented by the formula (Ibb) is preferably a compound represented by the formula (Inn), and the compound represented by the formula (Ib) is preferably a compound represented by the formula (In).

In the compounds represented by the formulas (Ibb) and (Ib), R ¹ is a lower alkyl group which may have a substituent, R ² is a hydrogen atom or a lower alkyl group, and Ar is a substituent. Is preferably a phenyl group, n is preferably 1, 2 or 3, R ¹ is a lower alkyl group which may have a substituent, and R ² is a hydrogen atom. More preferably, Ar is a phenyl group substituted with a halogen atom, and n is 2.

  As the compounds represented by the formulas (Icc) and (Ic), those in which Ar is a phenyl group which may have a substituent and n is 2 are preferable.

The leaving group represented by X ¹ is preferably, for example, a halogen atom (eg, chlorine, bromine, iodine, etc.), and particularly preferably a chlorine atom.

  In the compounds represented by the formula (I), (Iaa), (Ibb), (Icc), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig) When stereoisomers exist, each of the stereoisomers and a mixture of these stereoisomers are included in the present invention.

  Furthermore, when the compound represented by the formula (Iaa) is a compound represented by the formula (Icc) or (Inn), the compound represented by the formula (Ia) is represented by the formula (Ic) or (In). When the compound represented by formula (Ie) is the compound represented by formula (Ik) or (Ip), the compound represented by formula (Id) is represented by formula (Ir). And when the compound represented by the formula (Ig) is a compound represented by the formula (It), there are optical isomers based on the asymmetric carbon in the cycloalkene or cyclohexene ring, respectively. However, each of the optical isomers and a mixture of these optical isomers are included in the present invention.

  As the compound represented by the formula (I) or (Ia), specifically, a compound obtained in Reference Example B described later is used. Among them, <1> d-ethyl 6- [N- (2 , 4-difluorophenyl) sulfamoyl] -1-cyclohexene-1-carboxylate (d-ethyl 6- [N- (2,4-difluorophenyl) sulfamoyl] cyclohex-1-ene-1-carboxylate), <2 > Ethyl 6- [N- (2-chlorophenyl) sulfamoyl] -1-cyclohexene-1-carboxylate (ethyl 6- [N- (2-chlorophenyl) sulfamoyl] cyclohex-1-ene-1-carboxylate), < 3> ethyl 6- [N- (2-chloro-4-methylphenyl) sulfamoyl] -1-cyclohexene-1-carboxyler (Ethyl 6- [N- (2-chloro-4-methylphenyl) sulfamoyl] cyclohex-1-ene-1-carboxylate) or <4> d-ethyl 6- [N- (2-chloro-4- Fluorophenyl) sulfamoyl] -1-cyclohexene-1-carboxylate (ethyl (6R) -6- [N- (2-chloro-4-fluorophenyl) sulfamoyl] cyclohex-1-ene-1-carboxylate) or its Salt and the like are preferable.

  Compounds (I), (Iaa), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ibb), (I) used in the composition of the present invention Icc) (hereinafter abbreviated as the compound of the present invention) includes, for example, a salt with an inorganic base, a salt with an organic base, a salt with an inorganic acid, a salt with an organic acid, a salt with a basic or acidic amino acid, etc. Can be. Examples of the salt with an inorganic base include alkali metal salts such as sodium salt and potassium salt; alkaline earth metal salts such as calcium salt and magnesium salt; aluminum salt and ammonium salt. For example, a salt with trimethylamine, triethylamine, pyridine, picoline, ethanolamine, diethanolamine, triethanolamine, dicyclohexylamine, N, N′-dibenzylethylenediamine or the like is used. Examples of salts with inorganic acids include salts with hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, and examples of salts with organic acids include formic acid, acetic acid, trifluoroacetic acid, fumaric acid, Salts with oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, malic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid and the like are used. Examples of salts with basic amino acids include salts with arginine, lysine, ornithine, and examples of salts with acidic amino acids include salts with aspartic acid, glutamic acid, and the like.

The above compound can be produced, for example, by the method disclosed in WO99 / 46242.
(B) Compound of Formula (II) In the present specification, R ^{1 ′} is an aliphatic hydrocarbon group which may have a substituent, an aromatic hydrocarbon group which may have a substituent, and a substituent. A heterocyclic group which may have a group, a group represented by the formula: -OR ^{1a '} , or a formula:

In particular, a group represented by the formula: —OR ^{1a ′} is preferable.

Examples of the “aliphatic hydrocarbon group” of the “aliphatic hydrocarbon group optionally having substituents” represented by R ^{1 ′} include, for example, an alkyl group, a cycloalkyl group, a cycloalkylalkyl group, an alkenyl group. And an alkynyl group are preferred.

  Examples of the alkyl group include linear or branched alkyl groups having 1 to 20 carbon atoms (eg, methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, sec- A butyl group, a tert-butyl group, a pentyl group, a hexyl group, a heptyl group, an octyl group, a nonyl group, a decyl group, a dodecyl group, etc.), among others, for example, a lower alkyl group having 1 to 6 carbon atoms (eg, Methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, sec-butyl group, tert-butyl group and the like are preferred.

  As the cycloalkyl group, for example, a cycloalkyl group having 3 to 10 carbon atoms (eg, cyclopropyl group, cyclobutyl group, cyclopentyl group, cyclohexyl group, cycloheptyl group, cyclooctyl group, etc.) is preferable. And a cycloalkyl group having 3 to 6 carbon atoms (eg, cyclopropyl group, cyclobutyl group, cyclopentyl group, cyclohexyl group, etc.) are preferable.

  As the cycloalkylalkyl group, for example, a cycloalkylalkyl group having 4 to 12 carbon atoms (eg, cyclopropylmethyl group, cyclopentylmethyl group, cyclohexylmethyl group, cycloheptylmethyl group, etc.) and the like are preferable. A cycloalkylalkyl group having 4 to 8 carbon atoms (in particular, 4 to 7 carbon atoms) (eg, cyclopropylmethyl group, cyclopentylmethyl group, cyclohexylmethyl group, etc.) is preferred.

  As the alkenyl group, for example, a lower alkenyl group having 3 to 6 carbon atoms (eg, propenyl group, butenyl group, pentenyl group, etc.) and the like are preferable, and particularly, for example, a lower alkenyl group having 3 or 4 carbon atoms (eg, Propenyl group, butenyl group, etc.) are preferred.

  As the alkynyl group, for example, a lower alkynyl group having 3 to 6 carbon atoms (eg, propynyl group, butynyl group, pentynyl group, etc.) and the like are preferable. Group, butynyl group, etc.) are preferred.

As the “substituent” of the “aliphatic hydrocarbon group optionally having substituent (s)”, for example, a heterocyclic group, an oxo group, a hydroxyl group, a C _1-6 alkoxy group, C _3-10 (among others) C _3-6 ) cycloalkyloxy group, C _6-10 aryloxy group, C _7-19 (among others C _7-12 ) aralkyloxy group, heterocyclic oxy group, C _1-6 alkylthio group (the sulfur atom is C _3-10 (especially C _3-6 ) cycloalkylthio group (the sulfur atom may be oxidized), C _6-10 arylthio group (the sulfur atom is an oxide) C _7-19 (especially C _7-12 ) aralkylthio group (the sulfur atom may be oxidized), heterocyclic thio group, heterocyclic sulfinyl group, heterocyclic sulfonyl Base A nitro group, a halogen atom, a cyano group, a carboxyl _{group, C 1-10} (among others _{C 1-6)} alkoxy - carbonyl _{group, C 3-6} cycloalkyloxy - carbonyl _{group, C 6-10} aryloxy - carbonyl group, C _7-19 (among others _{C 7-12)} aralkyloxy - carbonyl group, a heterocyclic oxycarbonyl _{group, C 6-10} aryl - carbonyl _{group, C 1-6} alkanoyl _{group, C 3-5} alkenoyl _{group, C 6- 10} aryl-carbonyloxy group, C _2-6 alkanoyloxy group, C _3-5 alkenoyloxy group, optionally substituted carbamoyl group, optionally substituted thiocarbamoyl group, substituted A carbamoyloxy group optionally having a group, a C _1-6 alkanoylamino group, a C _6-10 aryl-carbonyl group Mino group, C _1-10 (among others C _1-6 ) alkoxy-carboxamide group, C _6-10 aryloxy-carboxamide group, C _7-19 (among others C _7-12 ) aralkyloxy-carboxamide group, C _{1 -10} (especially C _1-6 ) alkoxy-carbonyloxy group, C _6-10 aryloxy-carbonyloxy group, C _7-19 (particularly C _7-12 ) aralkyloxy-carbonyloxy group, C _3-10 (Especially C _3-6 ) cycloalkyloxy-carbonyloxy group, ureido group which may have a substituent, C _6-10 aryl group which may have a substituent, and the like are used.

  These substituents are substituted at substitutable sites of the “aliphatic hydrocarbon group”. The number of substituents is not limited to one, and there may be a plurality (2 to 4) of the same or different. Good.

Examples of the “C _1-6 alkoxy group” include methoxy group, ethoxy group, n-propoxy group, isopropoxy group, n-butoxy group, tert-butoxy group, n-pentyloxy group, n-hexyloxy group and the like. However, examples of the “C _3-10 cycloalkyloxy group” include a cyclopropyloxy group and a cyclohexyloxy group, and examples of the “C _6-10 aryloxy group” include a phenoxy group and a naphthyloxy group. , “C _7-19 aralkyloxy group” includes, for example, benzyloxy group, 1-phenylethyloxy group, 2-phenylethyloxy group, benzhydryloxy group, 1-naphthylmethyloxy group, etc. _1-6 the alkylthio group (the sulfur atom may be oxidized) ", for example, a methylthio group, e Thio group, n- propylthio group, n- butylthio group, methylsulfinyl group, methylsulfonyl group, the "C _3-10 cycloalkylthio group (the sulfur atom may be oxidized)", for example, A cyclopropylthio group, a cyclohexylthio group, a cyclopentylsulfinyl group, a cyclohexylsulfonyl group and the like, as the “C _6-10 arylthio group (the sulfur atom may be oxidized)”, for example, a phenylthio group, a naphthylthio group , Phenylsulfinyl group, phenylsulfonyl group, etc., as "C _7-19 aralkylthio group (the sulfur atom may be oxidized)", for example, benzylthio group, phenylethylthio group, benzhydrylthio group , Benzylsulfinyl group, benzylsulfonyl Etc., as the "halogen atom" include fluorine atom, a chlorine atom, a bromine atom, an iodine atom, - as the "C _1-10 alkoxy-carbonyl group", for example, a methoxycarbonyl group, an ethoxycarbonyl radical, n -Propoxycarbonyl group, isopropoxycarbonyl group, n-butoxycarbonyl group, isobutoxycarbonyl group, tert-butoxycarbonyl group and the like are exemplified by “C _3-6 cycloalkyloxy-carbonyl group” such as cyclopropyloxycarbonyl Group, cyclopentyloxycarbonyl group, cyclohexyloxycarbonyl group, norbornyloxycarbonyl group, etc., and “C _6-10 aryloxy-carbonyl group” includes, for example, phenoxycarbonyl group, naphthyloxycarbonyl group, etc. _{7- 9} aralkyloxy - carbonyl group ", for example, benzyloxycarbonyl group, benzhydryloxy group, such as 2-phenethyl oxycarbonyl group," C _6-10 aryl - as carbonyl group ", for example, benzoyl group , Naphthoyl group, phenylacetyl group, etc., as “C _1-6 alkanoyl group”, for example, formyl group, acetyl group, propionyl group, butyryl group, valeryl group, pivaloyl group and the like are referred to as “C _3-5 alkenoyl group”. the "example, an acryloyl group, a crotonoyl group," C _6-10 aryl - the carbonyloxy group ", for example, benzoyloxy group, naphthoyloxy group, phenylacetoxy group," C _2-6 Examples of the “alkanoyloxy group” include an acetoxy group , Propionyloxy group, butyryloxy group, valeryloxy group, pivaloyloxy group, etc. As the “C _3-5 alkenoyloxy group”, for example, acryloyloxy group, crotonoyloxy group and the like are used.

Examples of the “optionally substituted carbamoyl group” include C _1-4 alkyl (eg, methyl, ethyl, etc.), phenyl, C _1-7 acyl (eg, acetyl, propionyl, benzoyl, etc.), A carbamoyl group or a cyclic aminocarbonyl group which may be substituted with one or two substituents selected from C _1-4 alkoxy-phenyl (eg, methoxyphenyl etc.) and the like are used. For example, carbamoyl group, N-methylcarbamoyl group, N-ethylcarbamoyl group, N, N-dimethylcarbamoyl group, N, N-diethylcarbamoyl group, N-phenylcarbamoyl group, N-acetylcarbamoyl group, N-benzoylcarbamoyl Group, N- (p-methoxyphenyl) carbamoyl group, 1-pyrrolidinylcarbonyl group, Piperidino group, 1-piperazinylcarbonyl group, a morpholinocarbonyl group, etc. are used. The “optionally substituted thiocarbamoyl group” is, for example, substituted with 1 or 2 substituents selected from C _1-4 alkyl (eg, methyl, ethyl, etc.), phenyl and the like. An optional thiocarbamoyl group is used, and specifically, for example, a thiocarbamoyl group, an N-methylthiocarbamoyl group, an N-phenylthiocarbamoyl group, or the like is used. The “optionally substituted carbamoyloxy group” is, for example, substituted with 1 or 2 substituents selected from C _1-4 alkyl (eg, methyl, ethyl, etc.), phenyl and the like. Carbamoyloxy group which may be used, specifically, for example, carbamoyloxy group, N-methylcarbamoyloxy group, N, N-dimethylcarbamoyloxy group, N-ethylcarbamoyloxy group, N-phenylcarbamoyloxy group Etc. are used.

Examples of the “C _1-6 alkanoylamino group” include an acetamide group, a propionamide group, a butyroamide group, a valeramide group, a pivalamide group, and the like, and examples of the “C _6-10 aryl-carbonylamino group” include a benzamide group. , naphthamide group, a phthalimide group, - a _{"C 1-10} alkoxy-carboxamide group", for example, methoxy carboxamide _(CH 3 OCONH-) group, ethoxy carboxamide group, such as tert- butoxy carboxamide group, _{"C 6-} Examples of the “ ₁₀ aryloxy-carboxamide group” include a phenoxycarboxamide (C ₆ H ₅ OCONH—) group, and the “C _7-19 aralkyloxy-carboxamide group” includes, for example, a benzyloxycarboxamide (C ₆ H ₅ CH OCONH-) group, etc. benzhydryloxy carboxamide group, - a "C _1-10 alkoxy-carbonyloxy group", for example, a methoxycarbonyloxy group, an ethoxycarbonyloxy group, n- propoxycarbonyl group, isopropoxycarbonyl An oxy group, an n-butoxycarbonyloxy group, a tert-butoxycarbonyloxy group, an n-pentyloxycarbonyloxy group, an n-hexyloxycarbonyloxy group, and the like, as the “C _6-10 aryloxy-carbonyloxy group” For example, phenoxycarbonyl group, etc. naphthyloxycarbonyl group is - as the "C _7-19 aralkyloxy-carbonyloxy group", for example, benzyloxycarbonyl group, 1-phenylethyl oxycarboxin Aryloxy group, 2-phenylethyl oxycarbonyl group, etc. benzhydryloxy carbonyl group is - as the "C _3-10 cycloalkyloxy-carbonyloxy group", for example, cyclopropyloxycarbonyl group, cyclohexyloxycarbonyl An oxy group or the like is used.

Examples of the “ureido group optionally having substituent (s)” include 1 to 3 (among others, 1) selected from C _1-4 alkyl groups (eg, methyl group, ethyl group, etc.), phenyl groups, etc. Or a ureido group optionally substituted with two substituents, for example, ureido group, 1-methylureido group, 3-methylureido group, 3,3-dimethylureido group, 1,3-dimethylureido Group, 3-phenylureido group and the like are used.

  As the “substituent” of the “optionally substituted aliphatic hydrocarbon group”, a heterocyclic group, heterocyclic oxy group, heterocyclic thio group, heterocyclic sulfinyl group, heterocyclic sulfonyl group or heterocyclic oxy When a carbonyl group is used, the heterocyclic group represents a group capable of removing one hydrogen atom bonded to the heterocyclic ring, for example, a nitrogen atom (which may be oxidized), an oxygen atom, a sulfur atom A 5- to 8-membered ring group (particularly a 5- to 6-membered ring) group containing 1 to several, preferably 1 to 4 heteroatoms, or a condensed ring group thereof. Examples of such heterocyclic groups include pyrrolyl, pyrazolyl, imidazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, tetrazolyl, furyl, thienyl, oxazolyl, and isoxazolyl. Group, 1,2,3-oxadiazolyl group, 1,2,4-oxadiazolyl group, 1,2,5-oxadiazolyl group, 1,3,4-oxadiazolyl group, thiazolyl group, isothiazolyl group, 1,2,3- Thiadiazolyl group, 1,2,4-thiadiazolyl group, 1,2,5-thiadiazolyl group, 1,3,4-thiadiazolyl group, pyridyl group, pyridazinyl group, pyrimidinyl group, pyrazinyl group, indolyl group, pyranyl group, thiopyranyl group , Dioxynyl group, dioxolyl group, quinolyl group, pyrido [2,3-d] pyrimidyl group, 1, -, 1,6-, 1,7-, 1,8-, 2,6- or 2,7-naphthyridyl group, thieno [2,3-d] pyridyl group, benzopyranyl group, tetrahydrofuryl group, tetrahydropyranyl Group, dioxolanyl group, dioxanyl group and the like are used.

These heterocyclic groups are substituted with 1 to 3 substituents selected from C _1-4 alkyl (eg, methyl, ethyl, etc.), hydroxy, oxo, C _1-4 alkoxy (eg, methoxy, ethoxy, etc.), etc. It may be substituted at a substitutable site.

As the “C _6-10 aryl group” of the “ _optionally substituted C _6-10 aryl group”, for example, a phenyl group, a naphthyl group, and the like are used. The C _6-10 aryl group is the “substituent” of the “aliphatic hydrocarbon group _optionally having substituent (s)” (excluding the C _6-10 aryl group _optionally having substituent (s)). The substitutable portion may be substituted with a substituent selected from These substituents are substituted at substitutable positions of the C _6-10 aryl group, and the substituent is not limited to one, and there may be a plurality (2 to 4) of the same or different. Good.

  Further, the “aliphatic hydrocarbon group optionally having substituent (s)” may form a condensed ring group in which the substituent may be substituted together with the aliphatic hydrocarbon group, As such a condensed ring group, indanyl group, 1,2,3,4-tetrahydronaphthyl group and the like are used. In this fused ring group, a substitutable site may be substituted with a substituent selected from “substituent” of the “aliphatic hydrocarbon group optionally having substituent (s)”. These substituents are substituted at substitutable sites of the fused ring group, and the number of the substituents is not limited to one, and there may be a plurality (2 to 4) of the same or different.

The “aromatic hydrocarbon group” in the “aromatic hydrocarbon group optionally having substituents” represented by R ^{1 ′} is an aromatic hydrocarbon group having 6 to 14 carbon atoms (eg, phenyl group, A naphthyl group, a biphenyl group, an anthryl group, an indenyl group, etc.) are preferable, and an aryl group having 6 to 10 carbon atoms (eg, a phenyl group, a naphthyl group, etc.) is particularly preferable, and a phenyl group is particularly preferable. preferable.

Examples of the “substituent” in the “optionally substituted aromatic hydrocarbon group” represented by R ^{1 ′} include, for example, a halogen atom (eg, fluorine, chlorine, bromine, iodine, etc.), lower (C _1-4 ) alkyl group (eg, methyl group, ethyl group, propyl group, butyl group, etc.), lower (C _1-4 ) alkoxy group (eg, methoxy group, ethoxy group, propoxy group, butoxy group, etc.), lower (C _1-4 ) alkoxy-carbonyl group (eg, methoxycarbonyl group, ethoxycarbonyl group, propoxycarbonyl group, butoxycarbonyl group, etc.), carboxyl group, nitro group, cyano group, hydroxyl group, acylamino group (eg, acetylamino group) , An alkanoylamino group having 1 to 4 carbon atoms such as a propionylamino group and a butyrylamino group), and a cycloalkyl group having 3 to 6 carbon atoms Examples include cyclopropyl group, cyclopentyl group), an aryl group (e.g. having 6 to 10 carbon atoms, a phenyl group, a naphthyl group, an indenyl group and the like), halogeno lower (C _1-4) alkyl group (e.g., trifluoromethyl group ), Halogeno lower (C _1-4 ) alkoxy groups (eg, trifluoromethoxy group, 1,1,2,2-tetrafluoroethoxy group, 2,2,3,3,3-penta) Fluoropropoxy group, etc.), lower (C _1-4 ) alkylthio group (eg, methylthio group, ethylthio group, propionylthio group etc.), lower (C _1-4 ) alkylsulfonyl group (eg, methanesulfonyl group, ethanesulfonyl group) , propanesulfonyl etc. group), a lower _{(C 1-4)} alkanoyl group (eg formyl group, acetyl group, propionyl and the like groups), Member aromatic heterocyclic group (eg, 1,2,3-triazolyl group, 1,2,4-triazolyl group, tetrazolyl group, thiazolyl group, isothiazolyl group, oxazolyl group, isoxazolyl group, thiadiazolyl group, thienyl group, furyl group) Group), carbamoyl group, lower (C _1-4 ) alkyl-carbamoyl group (eg, methylcarbamoyl group, dimethylcarbamoyl group, propionylcarbamoyl group), lower (C _1-4 ) alkoxy-carbonyl-lower (C _{1 -4} ) alkyl-carbamoyl group (eg, butoxycarbonylmethylcarbamoyl group, ethoxycarbonylmethylcarbamoyl group, etc.), 1,3-diacylguanidino-lower (C _1-4 ) alkyl group (eg, 1,3-diacetylguanidinomethyl) 1,3-bis-tert-butoxycarbonylgua Nidinomethyl etc.), preferably halogen atoms (eg fluorine atom, chlorine atom, bromine atom, iodine atom etc.), lower (C _1-4 ) alkyl groups (eg methyl group, ethyl group, propyl group, butyl group) More preferably, a fluorine atom, a chlorine atom, or a methyl group is used.

  These substituents are substituted at substitutable sites of the aromatic hydrocarbon group, and the number of substituents is preferably 1 to 5, more preferably 1 to 3, and particularly preferably 1 to 2. When two or more substituents are present, these substituents may be the same or different.

The “heterocyclic group” in the “heterocyclic group optionally having substituent (s)” represented by R ^{1 ′} is, for example, a hetero atom such as a nitrogen atom (which may be oxidized), an oxygen atom, a sulfur atom, etc. Represents a 5- to 8-membered ring group (in particular, a 5- to 6-membered ring group) containing 1 to several, preferably 1 to 4, or a condensed ring group thereof. Examples of such heterocyclic groups include pyrrolyl, pyrazolyl, imidazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, tetrazolyl, furyl, thienyl, oxazolyl, and isoxazolyl. Group, 1,2,3-oxadiazolyl group, 1,2,4-oxadiazolyl group, 1,2,5-oxadiazolyl group, 1,3,4-oxadiazolyl group, thiazolyl group, isothiazolyl group, 1,2,3- Thiadiazolyl group, 1,2,4-thiadiazolyl group, 1,2,5-thiadiazolyl group, 1,3,4-thiadiazolyl group, pyridyl group, pyridazinyl group, pyrimidinyl group, pyrazinyl group, indolyl group, pyranyl group, thiopyranyl group , Dioxynyl group, dioxolyl group, quinolyl group, pyrido [2,3-d] pyrimidyl group, 1, -, 1,6-, 1,7-, 1,8-, 2,6- or 2,7-naphthyridyl group, thieno [2,3-d] pyridyl group, benzopyranyl group, tetrahydrofuryl group, tetrahydropyranyl Group, dioxolanyl group, dioxanyl group and the like are used. These heterocyclic groups are substituted with 1 to 3 substituents selected from C _1-4 alkyl (eg, methyl, ethyl, etc.), hydroxy, oxo, C _1-4 alkoxy (eg, methoxy, ethoxy, etc.), etc. It may be substituted at a substitutable site.

Examples of the “aliphatic hydrocarbon group optionally having substituent (s)” represented by R ^{1a ′} include, for example, the “aliphatic hydrocarbon optionally having substituent (s)” represented by R ^{1 ′} described above. Those similar to the “group” can be used. As R ^{1a ′} , for example, an optionally substituted lower alkyl group having 1 to 6 carbon atoms (eg, methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group) Tert-butoxycarbonylmethyl group, hydroxyethyl group, etc.) are preferably used, and among them, for example, methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group and the like are preferably used. . In particular, for example, a methyl group, an ethyl group, an n-propyl group and the like are preferable, and an ethyl group and the like are particularly preferable.

As the “aliphatic hydrocarbon group optionally having substituent (s)” represented by R ^{1b ′} and R ^{1c ′} , for example, “optionally substituted” represented by the aforementioned R ^{1 ′} The same “aliphatic hydrocarbon group” can be used. Examples of R ^{1b ′} and R ^{1c ′} include a lower alkyl group having 1 to 6 carbon atoms that may have a substituent (eg, methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group). Group, isobutyl group, tert-butoxycarbonylmethyl group, hydroxyethyl group, etc.) are preferably used. Among them, for example, methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, etc. Is preferably used. In particular, for example, a methyl group, an ethyl group, an n-propyl group and the like are preferable, and an ethyl group and the like are particularly preferable.

R ^{1 ′} is, for example, a lower alkyl group having 1 to 6 carbon atoms which may have a substituent (eg, methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group). Tert-butoxycarbonylmethyl group, hydroxyethyl group, etc.) are preferably used, and among them, for example, methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group and the like are preferably used. . In particular, for example, a methyl group, an ethyl group, an n-propyl group and the like are preferable, and an ethyl group and the like are particularly preferable.

Examples of the substituent in the methylene group which may have a substituent represented by Y include C _1-6 such as a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, and an isobutyl group. Alkyl groups such as hydroxy-substituted -C _1-6 alkyl groups such as hydroxymethyl group and hydroxyethyl group such as methoxycarbonylmethyl group, ethoxycarbonylmethyl group, tert-butoxycarbonylmethyl group, methoxycarbonylethyl group, ethoxycarbonylethyl group And a C _1-4 alkoxy-carbonyl-C _1-4 alkyl group such as tert-butoxycarbonylethyl group, and the like. Among them, a hydrogen atom and a methyl group are preferable, and a hydrogen atom is particularly preferable.

Examples of the substituent in the nitrogen atom which may have a substituent represented by Y include C _1-6 such as a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, and an isobutyl group. Alkyl groups such as hydroxy-substituted -C _1-6 alkyl groups such as hydroxymethyl group and hydroxyethyl group such as methoxycarbonylmethyl group, ethoxycarbonylmethyl group, tert-butoxycarbonylmethyl group, methoxycarbonylethyl group, ethoxycarbonylethyl group And a C _1-4 alkoxy-carbonyl-C _1-4 alkyl group such as tert-butoxycarbonylethyl group, and the like. Among them, a hydrogen atom and a methyl group are preferable, and a hydrogen atom is particularly preferable.

  The “aromatic hydrocarbon group” in the “optionally substituted aromatic hydrocarbon group” represented by Ar ′ is an aromatic hydrocarbon group having 6 to 14 carbon atoms (eg, phenyl group, A naphthyl group, a biphenyl group, an anthryl group, an indenyl group, etc.) are preferable, and an aryl group having 6 to 10 carbon atoms (eg, a phenyl group, a naphthyl group, etc.) is particularly preferable, and a phenyl group is particularly preferable. preferable.

Examples of the “substituent” in the “optionally substituted aromatic hydrocarbon group” represented by Ar ′ include, for example, a halogen atom (eg, fluorine, chlorine, bromine, iodine, etc.), lower (C _1-4 ) alkyl group (eg, methyl group, ethyl group, propyl group, butyl group, etc.), lower (C _1-4 ) alkoxy group (eg, methoxy group, ethoxy group, propoxy group, butoxy group, etc.), lower (C _1-4 ) alkoxy-carbonyl group (eg, methoxycarbonyl group, ethoxycarbonyl group, propoxycarbonyl group, butoxycarbonyl group, etc.), carboxyl group, nitro group, cyano group, hydroxyl group, acylamino group (eg, acetylamino group) , Alkanoylamino groups having 1 to 4 carbon atoms such as propionylamino group and butyrylamino group), cycloalkyl groups having 3 to 6 carbon atoms ( Examples, cyclopropyl group, cyclopentyl group, etc.), aryl groups having 6 to 10 carbon atoms (eg, phenyl group, naphthyl group, indenyl group, etc.), halogeno lower (C _1-4 ) alkyl groups (eg, trifluoromethyl group) ), Halogeno lower (C _1-4 ) alkoxy groups (eg, trifluoromethoxy group, 1,1,2,2-tetrafluoroethoxy group, 2,2,3,3,3-penta) Fluoropropoxy group, etc.), lower (C _1-4 ) alkylthio group (eg, methylthio group, ethylthio group, propionylthio group etc.), lower (C _1-4 ) alkylsulfonyl group (eg, methanesulfonyl group, ethanesulfonyl group) , Propanesulfonyl group, etc.), lower (C _1-4 ) alkanoyl group (eg, formyl group, acetyl group, propionyl group, etc.), 5 Member aromatic heterocyclic group (eg, 1,2,3-triazolyl group, 1,2,4-triazolyl group, tetrazolyl group, thiazolyl group, isothiazolyl group, oxazolyl group, isoxazolyl group, thiadiazolyl group, thienyl group, furyl group) Group), carbamoyl group, lower (C _1-4 ) alkyl-carbamoyl group (eg, methylcarbamoyl group, dimethylcarbamoyl group, propionylcarbamoyl group), lower (C _1-4 ) alkoxy-carbonyl-lower (C _{1 -4} ) alkyl-carbamoyl group (eg, butoxycarbonylmethylcarbamoyl group, ethoxycarbonylmethylcarbamoyl group, etc.), 1,3-diacylguanidino-lower (C _1-4 ) alkyl group (eg, 1,3-diacetylguanidinomethyl) 1,3-bis-tert-butoxycarbonylgua Jinomechiru etc.) and the like, preferably a halogen atom (e.g., fluorine atom, chlorine atom, bromine atom, iodine atom), a lower (C _1-4) alkyl group (e.g., methyl group, ethyl group, propyl group, butyl group More preferably, a fluorine atom, a chlorine atom, or a methyl group is used.

  These substituents are substituted at substitutable sites of the aromatic hydrocarbon group, and the number of substituents is preferably 1 to 5, more preferably 1 to 3, and particularly preferably 1 to 2. When two or more substituents are present, these substituents may be the same or different.

Specific examples of Ar ′ include a phenyl group, a halogenophenyl group, a lower (C _1-4 ) alkyl-phenyl group, a lower (C _1-4 ) alkoxy-phenyl group, and a lower (C _1-4 ) alkoxy. -Carbonylphenyl group, carboxylphenyl group, nitrophenyl group, cyanophenyl group, halogeno lower ( _C1-4 ) alkyl-phenyl group, halogeno lower ( _C1-4 ) alkoxy-phenyl group, lower ( _C1-4 ) An alkanoyl-phenyl group, a phenyl group substituted with a 5-membered aromatic heterocycle, a lower (C _1-4 ) alkoxy-carbonyl-lower (C _1-4 ) alkyl-carbamoylphenyl group, 1,3-diacylguanidino- lower _{(C 1-4)} alkyl - phenyl group, halogen and lower _{(C 1-4)} alkyl substituted phenyl group, a halo Emissions and lower (C _1-4) alkoxy - substituted phenyl group carbonyl, halogen and a phenyl group substituted by cyano, halogen and 5-membered aromatic heterocycle-substituted phenyl group, halogen and lower (C _1-4 ) A phenyl group substituted with alkoxy-carbonyl-lower ( _C1-4 ) alkyl-carbamoyl is used.

  Examples of the halogenophenyl group include 2,3-difluorophenyl group, 2,3-dichlorophenyl group, 2,4-difluorophenyl group, 2,4-dichlorophenyl group, 2,5-difluorophenyl group, 2,5 -Dichlorophenyl group, 2,6-difluorophenyl group, 2,6-dichlorophenyl group, 3,4-difluorophenyl group, 3,4-dichlorophenyl group, 3,5-difluorophenyl group, 3,5-dichlorophenyl group, 2 -Fluorophenyl group, 2-chlorophenyl group, 3-fluorophenyl group, 3-chlorophenyl group, 4-fluorophenyl group, 4-chlorophenyl group, 2-fluoro-4-chlorophenyl group, 2-chloro-4-fluorophenyl group 4-bromo-2-fluorophenyl group, 2,3,4-trifluorophenyl group 2,4,5-trifluorophenyl group, a 2,4,6-trifluorophenyl is used.

As the lower (C _1-4 ) alkyl-phenyl group, for example, 2-ethylphenyl group, 2,6-diisopropylphenyl group and the like are preferably used, and as the lower (C _1-4 ) alkoxy-phenyl group, For example, 4-methoxyphenyl and the like are preferably used.

As the lower (C _1-4 ) alkoxy-carbonylphenyl group, for example, 2-ethoxycarbonylphenyl group, 2-methoxycarbonylphenyl group, 4-methoxycarbonylphenyl group and the like are preferably used, and the halogeno lower (C _{1 -4} ) As the alkyl-phenyl group, for example, 2-trifluoromethylphenyl group is preferably used, and as the halogeno lower (C _1-4 ) alkoxy-phenyl group, for example, 2-trifluoromethoxyphenyl group is used. 4- (2,2,3,3,3-pentafluoropropoxy) phenyl group and the like are preferably used.

As the lower (C _1-4 ) alkanoyl-phenyl group, for example, 2-acetylphenyl group is preferably used, and as the phenyl group substituted with the 5-membered aromatic heterocyclic ring, for example, 4- ( 2H-1,2,3-triazol-2-yl) phenyl group, 4- (2H-tetrazol-2-yl) phenyl group, 4- (1H-tetrazol-1-yl) phenyl group, 4- (1H- 1,2,3-triazol-1-yl) phenyl group are preferably used, said lower _{(C 1-4)} alkoxy - carbonyl - lower _{(C 1-4)} alkyl - as a carbamoylphenyl group, for example, 4 - such as (N- ethoxycarbonyl-methylcarbamoyl) phenyl group are preferably used, the 1,3-diacyl-guanidino - lower _{(C 1-4)} alkyl - phenyl group Is then, for example, 4- (1,3-bis -tert- butoxycarbonyl-guanidino) phenyl group are preferably used.

Examples of the phenyl group substituted with the halogen and lower (C _1-4 ) alkyl include, for example, 2-fluoro-4-methylphenyl group, 2-chloro-4-methylphenyl group, 4-fluoro-2-methylphenyl group Group is preferably used, and as the phenyl group substituted with the halogen and lower (C _1-4 ) alkoxy-carbonyl, for example, 2-chloro-4-methoxycarbonylphenyl group is preferably used, and the halogen and cyano As the phenyl group substituted with, 2-chloro-4-cyanophenyl group or the like is preferably used, and as the phenyl group substituted with the halogen and a 5-membered aromatic heterocyclic ring, for example, 2-fluoro-4 - (IH-1,2,4-triazol-1-yl) phenyl and the like are preferably used, the halogen and lower (C _-4) alkoxy - carbonyl - lower _{(C 1-4)} - alkyl - as the phenyl group substituted with carbamoyl, for example, 2-chloro-4-(N-tert-butoxycarbonyl-methylcarbamoyl) phenyl group, 2- A chloro-4- (N-ethoxycarbonylmethylcarbamoyl) phenyl group and the like are preferably used.

Ar ′ is preferably a halogenophenyl group, a lower (C _1-4 ) alkyl-phenyl group, a phenyl group substituted by halogen and lower (C _1-4 ) alkoxy-carbonyl, or the like.

More specifically, Ar ′ includes, among others, a phenyl group, a phenyl group substituted with 1 to 3 (especially 1 to 2) halogens (eg, 2,3-difluorophenyl group, 2,3-dichlorophenyl). Group, 2,4-difluorophenyl group, 2,4-dichlorophenyl group, 2,5-difluorophenyl group, 2,5-dichlorophenyl group, 2,6-difluorophenyl group, 2,6-dichlorophenyl group, 3,4 -Difluorophenyl group, 3,4-dichlorophenyl group, 3,5-difluorophenyl group, 3,5-dichlorophenyl group, 4-bromo-2-fluorophenyl group, 2-fluorophenyl group, 2-chlorophenyl group, 3- Fluorophenyl group, 3-chlorophenyl group, 4-fluorophenyl group, 4-chlorophenyl group, 2-fluoro-4-chloro Phenyl, 2-chloro-4-fluorophenyl, 2,3,4-trifluorophenyl, 2,4,5-trifluorophenyl, etc.), halogen and lower (C _1-4 ) alkyl substituted And phenyl groups (eg, 2-chloro-4-methylphenyl group, 4-fluoro-2-methylphenyl group, etc.) are preferred. Among them, a phenyl group substituted with 1 to 3 (especially 1 to 2) halogens (eg, 2,3-dichlorophenyl group, 2,4-difluorophenyl group, 2,4-dichlorophenyl group, 2, 6-dichlorophenyl group, 2-fluorophenyl group, 2-chlorophenyl group, 3-chlorophenyl group, 2-chloro-4-fluorophenyl group, 2,4,5-trifluorophenyl group, etc.), halogen and lower (C _{1 -4} ) A phenyl group substituted with alkyl (eg, 2-chloro-4-methylphenyl group, 4-fluoro-2-methylphenyl group, etc.) and the like are preferable. In particular, Ar ′ has the formula:

Is preferably a group represented by the formula:

Is more preferable.
The halogen atom represented by R ³ in formula (c ′) and the substituent of ring B and the halogen atom represented by R ^3a and R ^3b in formula (c1 ′) are preferably a fluorine atom or a chlorine atom. Examples of the lower alkyl group represented by R ³ in the formula (c ′) include C _1-4 alkyl groups such as methyl, ethyl, and propyl. Among the groups represented by the formula (c ′), 2,4-difluorophenyl group, 2-chloro-4-fluorophenyl group, 2-methyl-4-chlorophenyl group and the like are preferable, and represented by the formula (c1 ′). Among these groups, 2,4-difluorophenyl group, 2-chloro-4-fluorophenyl group and the like are preferable.

  X represents a methylene group, a nitrogen atom, a sulfur atom or an oxygen atom, and among them, a nitrogen atom, a sulfur atom or an oxygen atom is preferable.

Ring A is a group represented by the formula: —CO—R ^{1 ′} (wherein R ^{1 ′} has the same meaning as described above) and a formula: —SO ₂ —Y—Ar ′ (wherein Y and Ar 'Is as defined above.) And is further substituted (1) an aliphatic hydrocarbon group which may have a substituent, and (2) a substituent. The aromatic hydrocarbon group may be represented by the formula (3): —OR ^{2 ′} (wherein R ^{2 ′} represents a hydrogen atom or an aliphatic hydrocarbon group which may have a substituent). And (4) a 5- to 8-membered ring optionally substituted with 1 to 4 substituents selected from halogen atoms, (1) an aliphatic hydrocarbon optionally having a substituent A group, (2) an optionally substituted aromatic hydrocarbon group and (4) 1 to 4 substituents selected from halogen atoms may be substituted 5-8 Ring is preferable.

Examples of the “aliphatic hydrocarbon group optionally having substituent (s)” represented by R ^{2 ′} include, for example, “aliphatic carbon optionally having substituent (s)” represented by R ^{1 ′} described above. The same “hydrogen group” can be used.

  These substituents can be substituted at substitutable positions on ring A. When X constituting the ring is a nitrogen atom or a methylene group, the nitrogen atom or the methylene group can be substituted. When ring A is substituted with a plurality of substituents, the types of these substituents may be the same or different. Two substituents may be substituted on the same carbon atom.

Examples of the “aliphatic hydrocarbon group optionally having substituent (s)” and the “aromatic hydrocarbon group optionally having substituent (s)” that are substituents of ring A include, for example, the aforementioned R ^{1 ′.} And the same as the “aliphatic hydrocarbon group optionally having substituent (s)” and “aromatic hydrocarbon group optionally having substituent (s)”.

Examples of the substituent for ring A include 1 or 2 C _1-6 alkyl groups (eg, C _1-4 alkyl groups such as methyl and tert-butyl groups), phenyl groups, and halogen atoms (eg, fluorine, chlorine). , Bromine, iodine, etc.) are preferably used.

  m represents an integer of 0 to 2, n ′ represents an integer of 1 to 3, and the sum of m and n ′ is 4 or less, preferably m is 1 and n ′ is 1.

As the compound represented by the formula (II), for example, the following compounds are preferable.
R ^{1 ′} is a group represented by the formula: —OR ^{1a ″} (R ^{1a ″} represents a C _1-6 alkyl group),

A group represented by the formula:

X represents a methylene or oxygen atom, Y represents a methylene or —NH—, Ar ′ has 1 or 2 substituents selected from the group consisting of a halogen atom and C _1-6 alkoxy. Compound (II) which is an optionally substituted phenyl group.
R ^{1 ′} is a group represented by the formula: —OR ^{1a ″} (R ^{1a ″} represents a C _1-6 alkyl group),

A group represented by the formula:

X is methylene and Y is methylene, or X is an oxygen atom, Y is —NH—, and Ar ′ may have two halogen atoms (examples) , 2-chloro-4-fluorophenyl group, etc.).
(3) ethyl 6- (benzylsulfonyl) -1-cyclohexene-1-carboxylate (compound 86), ethyl 6-[(4-methoxybenzyl) sulfonyl] -1-cyclohexene-1-carboxylate (compound 87), Ethyl 6-[(2,4-difluorobenzyl) sulfonyl] -1-cyclohexene-1-carboxylate (Compound 88), Ethyl 6-[(2-chloro-4-fluorobenzyl) sulfonyl] -1-cyclohexene-1 -Carboxylate (compound 89), ethyl (-)-6-[(2-chloro-4-fluorobenzyl) sulfonyl] -1-cyclohexene-1-carboxylate (compound 90), ethyl (+)-6- [ (2-Chloro-4-fluorobenzyl) sulfonyl] -1-cyclohexene-1-carboxy (Compound 91), ethyl 3-[(2,4-difluorophenyl) sulfamoyl] -3,6-dihydro-2H-pyran-4-carboxylate (compound 92) or ethyl 3-[(2-chloro- 4-Fluorophenyl) sulfamoyl] -3,6-dihydro-2H-pyran-4-carboxylate (Compound 93).
(4) Ethyl 6-[(2-chloro-4-fluorobenzyl) sulfonyl] -1-cyclohexene-1-carboxylate (compound 89), ethyl (+)-6-[(2-chloro-4-fluorobenzyl) ) Sulfonyl] -1-cyclohexene-1-carboxylate (compound 91) or ethyl 3-[(2-chloro-4-fluorophenyl) sulfamoyl] -3,6-dihydro-2H-pyran-4-carboxylate (compound) 93).

  Examples of the salt of the compound represented by formula (II) include a salt with an inorganic base, a salt with an organic base, a salt with an inorganic acid, a salt with an organic acid, and a salt with a basic or acidic amino acid. Examples of the salt with an inorganic base include alkali metal salts such as sodium salt and potassium salt, alkaline earth metal salts such as calcium salt and magnesium salt, aluminum salt, ammonium salt, etc. For example, salts with trimethylamine, triethylamine, pyridine, picoline, ethanolamine, diethanolamine, triethanolamine, dicyclohexylamine, N, N′-dibenzylethylenediamine, etc., and salts with inorganic acids include, for example, hydrochloric acid, hydrogen bromide Examples of salts with acids, nitric acid, sulfuric acid, phosphoric acid, and organic acids include formic acid, acetic acid, trifluoroacetic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, malic acid. , Methanesulfonic acid, benzenesulfonic acid, salt with p-toluenesulfonic acid, etc. are basic The salt of the amino acids, such as arginine, lysine, salts with ornithine. Examples of the salts with acidic amino acids such as aspartic acid, and salts with glutamic acid and the like.

  When a stereoisomer exists in the compound represented by the formula (II) or a salt thereof, each of the stereoisomers and a mixture of these stereoisomers are included in the present invention.

  Furthermore, optical isomers exist in the compound represented by the formula (II) or a salt thereof, and each of the optical isomers and a mixture of these optical isomers are included in the present invention.

  The above compound can be produced, for example, by the method disclosed in WO01 / 10826.

  The prodrug of the compound of the present invention or a salt thereof is a compound that is converted into the compound of the present invention by a reaction with an enzyme, gastric acid or the like under physiological conditions in vivo, that is, the enzyme is oxidized, reduced, hydrolyzed, etc. A compound that changes to the compound of the present invention, or a compound that undergoes hydrolysis or the like due to gastric acid or the like and changes to the compound of the present invention. The prodrug of the compound of the present invention is a compound in which the amino group of the compound of the present invention is acylated, alkylated or phosphorylated (eg, the amino group of the compound of the present invention is eicosanoylated, alanylated, pentylaminocarbonylated). , (5-methyl-2-oxo-1,3-dioxolen-4-yl) methoxycarbonylation, tetrahydrofuranylation, pyrrolidylmethylation, pivaloyloxymethylation, tert-butylated compounds, etc.); Compounds in which the hydroxyl group of the compound of the present invention is acylated, alkylated, phosphorylated or borated (eg, the hydroxyl group of the compound of the present invention is acetylated, palmitoylated, propanoylated, pivaloylated, succinylated, fumarylated, alanyl Compound, dimethylaminomethylcarbonylated compound, etc.); carboxyl of the compound of the present invention Esterified, amidated compounds (eg, the carboxyl group of the compound of the present invention is ethyl esterified, phenyl esterified, carboxymethyl esterified, dimethylaminomethyl esterified, pivaloyloxymethyl esterified, ethoxycarbonyloxy Ethyl esterification, phthalidyl esterification, (5-methyl-2-oxo-1,3-dioxolen-4-yl) methyl esterification, cyclohexyloxycarbonylethyl esterification, methylamidated compounds, etc.); It is done. These compounds can be produced from the compound of the present invention by a method known per se.

  In addition, the prodrug of the compound of the present invention is a compound that changes to the compound of the present invention under physiological conditions as described in Hirokawa Shoten 1990 "Pharmaceutical Development", Volume 7, pages 163 to 198. It may be.

  The compound of the present invention or a salt thereof or a prodrug thereof can be produced according to a method known per se, for example, the production method described in WO 99/46242 or a method analogous thereto.

  The compound of the present invention or a salt thereof or a prodrug thereof may be a hydrate or an anhydrate.

In addition, the compound of the present invention or a salt thereof or a prodrug thereof may be labeled with an isotope (eg, ³ H, ¹⁴ C, ³⁵ S, ¹²⁵ I, etc.).

  According to the composition of the present invention, the compound of the present invention having poor water solubility or a salt stable in the acidic region such as a salt or prodrug thereof can be effectively used as a component of the composition composed of an emulsifier.

  A compound that is stable in the acidic region, specifically, the compound of the present invention or a salt or prodrug thereof may be present in the oil phase in a liquid state or a solid state, and the composition of the present invention is an oil-in-water type. (O / W type) or S / O / W type emulsified composition.

  The composition of this invention can be manufactured using an emulsifier, for example.

  Specifically, the composition of the present invention comprises dispersed phase particles comprising an oil component, an emulsifier, and a compound stable in the acidic region (specifically, the compound of the present invention or a salt thereof or a prodrug thereof), It is comprised with the water containing the buffering agent with which the dispersed phase particle was disperse | distributed. The dispersed phase particle is a dispersed phase in which one of two liquids that do not mix with each other exists as fine particles in the other.

  As the oil component, all pharmaceutically acceptable fats and oils which are usually used for preparing a fat emulsion in the pharmaceutical technical field can be used. Examples of the fats and oils include vegetable oils, partially hydrogenated oils of vegetable oils, fats and oils obtained by transesterification (simple glyceride or mixed glyceride), and medium chain fatty acid glycerin esters. Can be mentioned.

  The fats and oils include glycerin esters of fatty acids having about 6 to 30 carbon atoms (preferably about 6 to 22 carbon atoms). Examples of the fatty acids include saturated fatty acids such as caproic acid, caprylic acid, capric acid, lauric acid, myristic acid, palmitic acid, stearic acid, and behenic acid, palmitooleic acid, oleic acid, linoleic acid, arachidonic acid, eicoid. Examples are unsaturated fatty acids such as sapentanoic acid and docosahexaenoic acid.

  Among the vegetable oils, preferable oil components include, for example, vegetable oils such as soybean oil, cottonseed oil, rapeseed oil, peanut oil, safflower oil, sesame oil, rice bran oil, corn germ oil, sunflower oil, poppy oil, olive oil, and the like. . Of these vegetable oils, soybean oil and the like are preferably used.

  Further, triglycerides of medium chain fatty acids having about 6 to 14 carbon atoms (preferably about 8 to 12 carbon atoms) can be used as fats and oils. Preferred medium-chain fatty acid glycerin esters include, for example, caprylic / capric triglycerides such as “Miglyol 810” and “Miglyol 812” (both available from Huls, Mitsuba Trading Co., Ltd.). triglycerides), for example, caprylic acid triglycerides (glycerin tricaprylic acid ester) such as “Panasate 800” (manufactured by NOF Corporation).

  The amount of the oil component used in the composition of the present invention is, for example, about 1 to about 30% by weight, preferably about 2 to about 25% by weight, and more preferably about 2.5 to about 22%, based on the entire composition. About 5% by weight.

  As the emulsifier, any pharmaceutically acceptable emulsifier can be used. In particular, pharmaceutically acceptable phospholipids and nonionic surfactants are preferred. The emulsifiers can be used alone or as a mixture of two or more.

  Examples of phospholipids include phospholipids obtained in nature (eg, egg yolk lecithin, soybean lecithin, etc.), hydrogenated products thereof, or phospholipids obtained synthetically (eg, phosphatidylcholine, phosphatidyl). Ethanolamines, phosphatidic acid, phosphatidylserine, phosphatidylinositol, phosphatidylglycerol, etc.). Of these phospholipids, egg yolk lecithin, soybean lecithin, and phosphatidylcholine derived from egg yolk and soybean are preferable. A particularly preferred phospholipid is lecithin. Further, among the synthetic phospholipids, anionic phospholipids are preferable, and specific examples of the anionic synthetic phospholipids include dimyristoyl phosphatidyl glycerol, dipalmitoyl phosphatidyl glycerol, distearoyl phosphatidyl glycerol, Oleoylphosphatidylglycerol, oleoylpalmitoylphosphatidylglycerol, dioctanoylphosphatidic acid, didecanoylphosphatidic acid, dilauroylphosphatidic acid, dimyristoylphosphatidic acid, dipalmitoylphosphatidine Acid, diheptadecanoyl phosphatidic acid, distearoyl phosphatidic acid, dioleoylphosphatidic acid, arachidonyl stearoyl phosphatidic acid, dipalmitoyl phosphatase Dilserine, dioleoylphosphatidylserine, dimyristoylphosphatidylinositol, dipalmitoylphosphatidylinositol, distearoylphosphatidylinositol, dioleoylphosphatidylinositol, dimyristoylphosphatidylserine, distearoylphosphati Anionic synthetic phospholipids such as dilserine are used, and dimyristoyl phosphatidylglycerol is particularly preferred.

  These anionic synthetic phospholipids can be chemically synthesized using a method known per se, or can be obtained by purification.

  As the nonionic surfactant, a polymer surfactant having a molecular weight of about 800 to 20,000, for example, polyoxyethylene-polyoxypropylene copolymer, polyoxyethylene alkyl ether, polyoxyethylene alkyl aryl ether, hydrogenated castor oil Examples thereof include polyoxyethylene derivatives, polyoxyethylene sorbitan derivatives, polyoxyethylene sorbitol derivatives, polyoxyethylene alkyl ether sulfates, and the like.

  The emulsifiers of the phospholipid and the nonionic surfactant can be used alone or as a mixture of two or more. Commercially available phospholipids may also be used.

  The total amount of emulsifier used in the composition of the present invention is usually about 0.1 to about 10% (W / V), preferably about 0.2 to about 7% (W / V) based on the total composition. More preferably, it is about 0.5 to about 5% (W / V). Among these, the anionic synthetic phospholipid is about 0.0001 to about 5% (W / V) with respect to the whole composition.

  In the composition of the present invention, the ratio of the emulsifier to the oil component is, for example, about 0.1 to about 150% by weight, preferably about 0.5 to about 125% by weight, more preferably about 1 to about 100% by weight. It is. The emulsifier is usually used in an amount of about 1 to about 15% by weight, particularly about 1 to about 10% by weight, based on the oil component.

  If the water used by this invention is accept | permitted as a pharmaceutical, there will be no restriction | limiting in particular, For example, purified water, water for injection (distilled water for injection), etc. are mentioned. There are no particular restrictions when manufacturing non-pharmaceutical products.

  The amount of water used in the composition of the present invention is usually about 40 to about 99% (W / V), preferably about 55 to about 98.8% (W / V), based on the total composition. .

  The composition of the present invention can be prepared by emulsifying the emulsified mixture of the compound of the present invention or a salt thereof or a prodrug (main drug), an oil component and an emulsifier with water and emulsifying the buffer before emulsification. You may add to an aqueous phase and may add to an emulsified composition after emulsification. If necessary, a stabilizer for improving the stability of the active ingredient, an isotonic agent for adjusting the osmotic pressure, an emulsification auxiliary agent for improving the emulsifying power, and improving the stability of the emulsifier. An additive such as an emulsion stabilizer may be added.

  Examples of the stabilizer include antioxidants (for example, ascorbic acid, tocopherol, sorbic acid, retinol, etc.), chelating agents (for example, edetic acid, citric acid, tartaric acid, and salts thereof) and the like. The amount of the stabilizer used is usually about 0.00001 to about 10% (W / V), preferably about 0.0001 to about 5% (W / V) with respect to the entire composition of the present invention. is there.

  Isotonic agents include, for example, glycerin, sugar alcohol, monosaccharide, disaccharide, amino acid, dextran, albumin and the like. These isotonic agents can be used singly or in combination.

  Examples of the emulsification aid include fatty acids having about 6 to 30 carbon atoms, salts of these fatty acids, monoglycerides of the fatty acids, and the like. Examples of the fatty acid include caproic acid, capric acid, caprylic acid, lauric acid, myristic acid, palmitic acid, stearic acid, behenic acid, palmitooleic acid, oleic acid, linoleic acid, arachidonic acid, eicosapentanoic acid, Docosahexaenoic acid and the like are included, and the fatty acid salt includes, for example, alkali metal salts such as sodium salt and potassium salt, calcium salt and the like.

  As the emulsion stabilizer, for example, cholesterol, cholesterol ester, tocopherol, albumin, fatty acid amide derivative, polysaccharide, derivative of fatty acid ester of polysaccharide, and the like can be used.

  The concentration of a compound that is stable in the acidic region in the composition of the present invention (hereinafter abbreviated as the compound of the present invention or a salt or prodrug thereof) varies depending on the pharmacological activity or blood kinetics of the compound, but is usually about 0. It is about 001 to about 5% (W / V), preferably about 0.01 to about 2% (W / V), more preferably about 0.1 to about 1.5% (W / V). Further, the content of the compound of the present invention or a salt or prodrug thereof in the composition of the present invention is set to about 1 to about 5000 mg, preferably about 10 to about 2000 mg, preferably about 100 to about 1500 mg in 100 ml of the composition. You can also In addition, the content of the compound of the present invention or a salt or prodrug thereof is about 0.001 to about 95% by weight, preferably about 0.01 to about 30% by weight, more preferably about 0.0. It can also be adjusted to 1 to about 3% by weight.

  The ratio (% by weight) of the compound of the present invention or a salt or prodrug thereof to the dispersed phase composed of an oil component and an emulsifier is usually about 0.0047 to about 24%, preferably about 0.047 to It is about 9.4%.

  The composition of the present invention has a pH adjusted to about 3.7 to about 5.5, preferably about 3.7 to about 5.0, more preferably about 4.0 to about 5.0.

  As the pH adjuster, for example, phosphoric acid, carbonic acid, citric acid, hydrochloric acid, sodium hydroxide and the like are used, and hydrochloric acid, sodium hydroxide and the like are particularly preferable.

  As the buffer, any pharmaceutically acceptable buffer can be used. For example, acetic acid, glacial acetic acid, lactic acid, citric acid, phosphoric acid, carbonic acid, histidine, glycine, barbital, phthalic acid, adipic acid, ascorbic acid, maleic acid, succinic acid, tartaric acid, glutamic acid, benzoic acid, aspartic acid and its salts (Eg, potassium, sodium, etc.), specifically sodium acetate, sodium lactate, sodium citrate, disodium monohydrogen phosphate, monosodium dihydrogen phosphate, sodium carbonate, sodium bicarbonate, hydrochloric acid and sodium hydroxide A buffering agent containing such as constituents is preferred. Moreover, you may use combining each buffering agent. In particular, it is preferable to use one or two or more buffers selected from an acetate buffer, a glacial acetate buffer, a lactic acid buffer, a citrate buffer, and a phosphate buffer.

  As the buffer, (i) a combination of acetic acid or glacial acetic acid and sodium acetate (acetic acid buffer or glacial acetic acid buffer) or (ii) a combination of lactic acid and sodium lactate (lactic acid buffer) is preferably used.

  The concentration of the buffer is usually about 100 mM or less, specifically about 0.1 mM to about 100 mM, preferably about 0.2 to about 50 mM, more preferably about 5 mM to about 40 mM.

  The pH adjuster is an acid or alkali compound added to adjust the pH of the solution to a target pH.

  In general, the amount of the pH adjusting agent to be added to the injection is very small, and the amount of sodium hydroxide as the pH adjusting agent in the fat emulsion commercially available in Japan is about 0.5 mM or less. Although the pH can be adjusted to the intended pH at the time of adjusting the solution, the pH of the solution is likely to change due to the addition of acid or alkali, and it is difficult to maintain the pH.

  The buffering agent is a compound having an action of relaxing a change in pH when an acid or an alkali is added, that is, a buffering action. In many cases, it is a mixed solution of a weak acid and its salt, or a weak base and its salt.

  In the emulsified composition of the present invention, it is possible to maintain the pH of the emulsified composition constant during high-pressure steam sterilization and long-term storage by blending a buffering agent without being affected by the generation of free fatty acids. is there.

  The amount of the buffer used in general injections is large for the purpose of buffering. For example, the amount of acetate buffer in a solution injection commercially available in Japan is about 0.2 mM. ˜about 100 mM.

  The composition of the present invention is preferably used, for example, as an injectable composition.

  The composition of the present invention can basically be produced according to a known method or a method analogous thereto. In particular, a conventional emulsification technique can be used for emulsification, but it is preferable that the compound of the present invention or a salt or prodrug thereof is previously dissolved or dispersed in an oil component. That is, an O / W type or S / O type is obtained by dispersing a mixed liquid of a dispersed phase (1) containing an oil component and an emulsifier and the compound of the present invention or a salt or prodrug (2) thereof in water. A composition composed of a / W type emulsion can be produced. The buffer may be added to the aqueous phase before emulsification or to the emulsion after emulsification. The mixed liquid to be emulsified can be produced by mixing the water phase with the oil phase or mixing the oil phase with the water phase. Additives such as stabilizers and tonicity agents can be added to either the aqueous phase or the oil phase.

  In a more preferable method, for example, a non-homogeneous mixture of a liquid mixture containing an additive such as an active ingredient, an oil component, an emulsifier, and an isotonic agent if necessary, and water containing a buffering agent is obtained using an emulsifier. Homogenize to prepare a crude emulsion, add water if necessary, further homogenize using the above emulsifier, and then remove large particles with a filtering means such as a filter if necessary. To prepare an oil-in-water composition. In many cases, the liquid mixture is heated or heated to a temperature of about 30 to about 90 ° C., preferably about 40 to about 80 ° C. to dissolve or disperse the active ingredient. In addition, as an emulsifier for emulsifying the heterogeneous mixture of the mixture and water, a conventional apparatus, for example, a homogenizer such as a pressure jet homogenizer or an ultrasonic homogenizer, or a homomixer such as a high-speed rotary mixer Etc. can be used. In order to remove large particles in the emulsifier, the homogenized emulsion can be subjected to filtration means such as a filter. The pore size of the filter used is, for example, about 0.8 to about 20 μm, preferably about 1 to about 10 μm.

  In the composition of the present invention, the particle size distribution of the dispersed phase in which the compound of the present invention or a salt or prodrug thereof is dissolved is, for example, about 0.01 to about 7 μm, preferably about 0.02 to about 5 μm. There are many cases. Further, from the viewpoint of emulsion stability and biodistribution after administration, the average particle size of the dispersed phase particles in which the compound of the present invention or a salt thereof or a prodrug thereof is dissolved is, for example, about 0.025 to about 0.00. It is about 7 μm, preferably about 0.05 to about 0.4 μm.

  The average particle diameter used in the present specification means an average particle diameter based on a volume distribution, and an average particle diameter of a dispersed phase particle measured by a laser diffraction particle size distribution measuring apparatus using a laser diffraction / confusion method as a measurement principle. It is.

  The composition of the present invention can remove pyrogen using a method known per se.

  The composition of the present invention is sterilized and sealed after substituting with nitrogen gas as necessary.

  Since the composition of the present invention is adjusted to a pH of about 3.7 to about 5.5 by adding a buffering agent, the composition of the present invention can be used after sterilization in an autoclave or after storage for a long period of time. The pH and the average particle diameter of the dispersed phase particles hardly change and are stable. Therefore, the stability of the composition of the present invention and a compound that is stable in the acidic region (particularly the compound of the present invention or a salt thereof or a prodrug thereof) is excellent. Further, even after the composition of the present invention is sterilized by an autoclave or the like and stored for a long period of time, no visible oil droplets are formed, that is, the dispersed phase particles and the dispersed phase particles are dispersed. Water is stable without phase separation.

  In addition, since the emulsion composition of the present invention can be adjusted to a pH of about 3.7 to about 5.5 by adding a buffering agent to form a stable emulsion composition, An optimum pH can be selected according to other conditions such as stability. Therefore, even when there are other conditions that can be overcome by adjusting the pH in the range of about 3.7 to about 5.5, such as when affecting the stability of the emulsified composition, select the pH adjustment. Thus, an emulsified composition suitable for various conditions can be obtained.

  Furthermore, the emulsified composition of the present invention exhibits a long-term stability of 24 months, which is over 18 months of the typical use period for emulsion formulations.

  Furthermore, the emulsion composition of the present invention can increase the concentration of a compound that is stable in the acidic region (particularly, the compound of the present invention or a salt thereof or a prodrug thereof). Combining optimal selection of emulsifiers, addition of nonionic surfactants such as polyoxyethylene compounds (polyethylene glycol, polysorbate, etc.), modification to the surface of dispersed phase particles, control of particle size of dispersed phase particles, etc. Thus, it is possible to improve the retention in blood, the blood vessel permeability, and the migration to an inflammatory site. Therefore, the pharmacokinetics and biodistribution of the compound of the present invention, a salt thereof, or a prodrug thereof can be improved, and targeting can be performed, thereby enabling administration of a drug that is more effective and suppresses side effects. Therefore, the emulsion composition of the present invention is particularly useful for treating a target disease by intravenous administration.

  When the compound stable in the acidic region is the compound in the present invention or a salt thereof or a prodrug thereof, the compound in the present invention or a salt thereof or a prodrug thereof has a low toxicity and a nitric oxide (NO) production inhibitory action and TNF-α. , IL-1, IL-6 and other inflammatory cytokine production suppressive action, the composition of the present invention is not only used for sepsis including severe sepsis, but also for mammals (eg, cats, cows, dogs, horses). Diseases such as sepsis, endotoxin shock, exotoxin shock, heart disease, autoimmune disease, inflammatory disease, central nervous system disease, infectious disease, septic shock, hypoimmune function, etc. Systemic inflammatory response syndrome (SIRS), compensatory anti-inflammatory response syndrome (CARS), burns, trauma, postoperative complications, Failure, shock, hypotension, rheumatoid arthritis, osteoarthritis, gastritis, ulcerative colitis, peptic ulcer, stressed gastric ulcer, Crohn's disease, autoimmune disease, tissue damage and rejection after organ transplantation, ischemia reperfusion injury , Acute coronary microvascular embolism, shock vascular embolism (disseminated intravascular coagulation (DIC), etc.), ischemic encephalopathy, arteriosclerosis, pernicious anemia, Fanconi anemia, sickle cell anemia, pancreatitis, nephrotic syndrome , Nephritis, renal failure, insulin-dependent diabetes, non-insulin-dependent diabetes, hepatic porphyria, alcoholism, Parkinson's disease, chronic leukemia, acute leukemia, tumor, myeloma, infant and adult respiratory distress syndrome, emphysema, dementia , Alzheimer's disease, multiple sclerosis, vitamin E deficiency, aging, sunburn, muscular dystrophy, myocarditis, cardiomyopathy, myocardial infarction Obstruction, myocardial infarction sequelae, osteoporosis, pneumonia, hepatitis, psoriasis, pain, cataract, influenza infection, malaria, human immunodeficiency virus (HIV) infection, radiation injury, burn, in vitro fertilization efficiency, hypercalcemia, rigidity Spondylitis, osteopenia, osteo-Behcet's disease, osteomalacia, fracture, acute bacterial meningitis, Helicobacter pylori infection, invasive staphylococcal infection, tuberculosis, systemic fungal infection, herpes simplex virus infection Symptom, varicella-zoster virus infection, human papillomavirus infection, acute viral encephalitis, encephalitis, meningitis, immune function decline due to infection, asthma, atopic dermatitis, allergic rhinitis, reflux esophagitis, fever Hypercholesterolemia, hyperglyceridemia, hyperlipidemia, diabetic complications, diabetic nephropathy, diabetic neuropathy, diabetic retinopathy, Wind, stomach atony, hemorrhoids, systemic lupus erythematosus, spinal cord injury, insomnia, schizophrenia, hemorrhoids, cirrhosis, liver failure, unstable angina, valvular disease, dialysis thrombocytopenia or hypotension, acute illness Hematologic stroke, acute cerebral thrombosis, cancer metastasis, bladder cancer, breast cancer, cervical cancer, colon cancer, gastric cancer, ovarian cancer, prostate cancer, small cell lung cancer, non-small cell lung cancer, malignant melanoma, Hodgkin's disease, non-Hodgkin It can also be used effectively for the prevention and treatment of side effects caused by the administration of lymphoma, anticancer agents and immunosuppressive agents.

  Furthermore, the composition of the present invention is also useful as a TLR signal inhibitor. “TLR signal” refers to signal transmission for an arbitrary Toll-like receptor to recognize a microbial cell component and induce a biological defense reaction. For example, signal transmission via known TLR1 to TLR10 Can be mentioned.

  Since the compound or a salt thereof or a prodrug thereof in the present invention has a low toxicity and a TLR signal inhibitory action, and suppresses inflammatory mediators such as NO and / or cytokine production, the composition of the present invention is capable of It is useful for the prevention and treatment of diseases caused by changes, such as organ damage. The term “organ” as used herein refers to various organs of the central nervous system, circulatory system, respiratory system, bone / joint system, digestive system, or kidney / urinary system.

The composition of the present invention results from a change in TLR signal as a TLR signal inhibitor.
(1) Central nervous system diseases [(i) neurodegenerative diseases (eg, senile dementia, Alzheimer's disease, Down syndrome, Parkinson's disease, Creutzfeldt-Jakob disease, amyotrophic spinal sclerosis, diabetic neuropathy, etc.), (ii) Neuropathy during cerebral circulatory disorder (eg, cerebral infarction, cerebral hemorrhage, cerebral circulatory failure associated with cerebral arteriosclerosis), head injury / spinal cord injury, sequelae of encephalitis, or cerebral palsy, (iii) memory Disorders (eg, senile dementia, amnesia, etc.)), especially Alzheimer's disease,
(2) Cardiovascular disease [(i) acute coronary syndrome such as acute myocardial infarction, unstable angina, (ii) peripheral arterial occlusion, (iii) coronary intervention (percutaneous coronary angioplasty (PTCA) Stenosis after atherectomy (DCA), stent placement, etc., (iv) restenosis after coronary artery bypass surgery, (v) intervention in other peripheral arteries (angioplasty, atherectomy, stent placement, etc.) and bypass Restenosis after surgery, (vi) ischemic heart disease such as myocardial infarction, angina pectoris, (vii) intermittent claudication, (viii) stroke (cerebral infarction, cerebral embolism, cerebral hemorrhage, etc.), (ix) rakune infarction, (x) cerebrovascular dementia, (xi) arteriosclerosis (eg, atherosclerosis, etc.) and diseases caused by these (eg, ischemic heart disease such as myocardial infarction and cerebral blood vessels such as cerebral infarction and stroke) Disorders), (xii) heart failure, (xiii) arrhythmia, (xiv) motion Progress of sclerosis plaques, (xv) thrombus formation, (xvi) hypotension, (xvii) shock, (such as disseminated intravascular coagulation (DIC)) (xviii) shockable embolization], particularly arteriosclerosis,
(3) Respiratory system diseases (respiratory distress syndrome, respiratory failure, emphysema, pneumonia, bronchitis, bronchiolitis, etc.),
(4) Bone and joint diseases (such as rheumatoid arthritis, osteoporosis, osteomalacia, osteopenia, bone Behcet's disease), especially rheumatoid arthritis,
(5) Gastrointestinal / hepatobiliary pancreatic diseases [ulcerative colitis, gastritis, peptic ulcer, cirrhosis, liver failure, hepatitis, cholecystitis, pancreatitis, etc.], especially ulcerative colitis,
(6) Kidney / urinary tract diseases (nephritis, renal failure, cystitis, etc.)
Or it is useful for prevention / treatment of diseases (multi-organ failure, etc.) in which these are combined. The composition of the present invention is also useful as a TLR signal inhibitor for the prevention and treatment of infections caused by changes in TLR signals, particularly sepsis (severe sepsis) associated with organ damage.

  The dosage of the composition of the present invention depends on the type, age, body weight, symptom, dosage form, administration method, administration period, etc. of the compound that is stable in the acidic region (particularly the compound of the present invention or a salt thereof or a prodrug thereof). Although different, for example, about 0.01 to about 1000 mg / kg, preferably about 0.1 per day, as a compound (Iaa) or (Ie) of the present invention per person with sepsis (adult, body weight about 60 kg). 01 to about 100 mg / kg, more preferably about 0.1 to about 100 mg / kg, especially about 0.1 to about 50 mg / kg, especially about 1.0 to about 30 mg / kg once a day It is administered intravenously in divided doses. Moreover, you may administer continuously by infusion. Of course, as described above, the dosage varies depending on various conditions. Therefore, a dosage smaller than the dosage may be sufficient, or the dosage may need to be administered beyond the range.

  The composition of the present invention can be used, for example, in combination with a drug other than the compound of the present invention or a salt thereof or a prodrug thereof.

  Examples of a drug that can be used in combination with the compound of the present invention or a salt thereof or a prodrug thereof (hereinafter sometimes abbreviated as a concomitant drug) include, for example, antibacterial drugs, antifungal drugs, nonsteroidal anti-inflammatory drugs, steroid drugs, Anticoagulant, antiplatelet agent, thrombolytic agent, immunomodulator, antiprotozoal agent, antibiotics, antitussive and expectorant, sedative, anesthetic, antiulcer agent, antiarrhythmic agent, antihypertensive diuretic, mental stability Drugs, antipsychotics, antitumor drugs, antihyperlipidemic drugs, muscle relaxants, antiepileptic drugs, antidepressants, antiallergic drugs, cardiotonic drugs, arrhythmia drugs, vasodilators, vasoconstrictors, antihypertensive diuresis Drugs, antidiabetic drugs, narcotic antagonists, vitamin drugs, vitamin derivatives, arthritis drugs, antirheumatic drugs, antiasthma drugs, frequent urinary / urinary incontinence drugs, atopic dermatitis drugs, allergic rhinitis drugs, pressurization Drugs, endotoxin antagonists Examples include antibodies, signal transduction inhibitors, inflammatory mediator action inhibitors, inflammatory mediator action inhibitory antibodies, anti-inflammatory mediator action inhibitory drugs, anti-inflammatory mediator action inhibitory antibodies, among others antibacterial and antifungal agents Nonsteroidal anti-inflammatory drugs, steroid drugs, anticoagulants and the like are preferred. Specific examples include the following.

(1) Antibacterial agents <1> sulfa drugs Sulfametisol, sulfisoxazole, sulfamonomethoxine, sulfamethizol, salazosulfapyridine, silver sulfadiazine and the like.
<2> Quinoline antibacterial agents Nalidixic acid, pipemidic acid trihydrate, enoxacin, norfloxacin, ofloxacin, tosufloxacin tosylate, ciprofloxacin hydrochloride, romefloxacin hydrochloride, sparfloxacin, fleroxacin and the like.
<3> Antituberculosis drugs Isoniazid, ethambutol (ethambutol hydrochloride), paraaminosalicylic acid (calcium paraaminosalicylate), pyrazinamide, etionamide, prothionamide, rifampicin, streptomycin sulfate, kanamycin sulfate, cycloserine and the like.
<4> Anti-acid-fast bactericides such as diphenylsulfone and rifampicillin.
<5> Antiviral drugs idoxuridine, acyclovir, vitarabine, ganciclovir, etc.
<6> Anti-HIV drugs Zidovudine, didanosine, zalcitabine, indinavir sulfate ethanol adduct, ritonavir and the like.
<7> Antispirocheta drugs <8> Antibiotics Tetracycline hydrochloride, ampicillin, piperacillin, gentamicin, dibekacin, cannendomycin, libidomycin, tobramycin, amikacin, fradiomycin, sisomycin, tetracycline, oxytetracycline, loritetracycline, doxycycline, ampicillin, Piperacillin, ticarcillin, cephalothin, cefapirin, cephaloridine, cefaclor, cephalexin, cefloxazine, cefadroxyl, cefamandol, cephoam, cefuroxime, cefothium, cefothium hexetyl, cefuroxime xetilyl, cefdinir ceftefirfide , Cefmenoxime, cefpodoxime proxet Cefpirom, cefazoplan, cefepime, cefsulosin, cefmenoxime, cefmetazole, cefminox, cefoxitin, cefbuperazone, latamoquinacef, flomoxef, cefazoline, cefotaxime, cefoperazone, cefizoxim, cefazoxine,・ Of Antibiotics (J. Antibiotics), 38,877-885 (1985)].

(2) Antifungal <1> Polyethylene antibiotics (eg, amphotericin B, nystatin, tricomycin)
<2> Griseofulvin, pyrrolnitrin, etc. <3> Cytosine antimetabolite (eg, flucytosine)
<4> Imidazole derivatives (eg, econazole, clotrimazole, miconazole nitrate, bifonazole, croconazole)
<5> Triazole derivatives (eg, fluconazole, itraconazole, azole compounds [2-[(1R, 2R) -2- (2,4-difluorophenyl) -2-hydroxy-1-methyl-3- (1H-1 , 2,4-triazol-1-yl) propyl] -4- [4- (2,2,3,3-tetrafluoropropoxy) phenyl] -3 (2H, 4H) -1,2,4-triazolone)
<6> Thiocarbamic acid derivatives (eg, trinaphthol)
<7> Echinocandin derivatives (eg, caspofandine, micafungin, anidurafungin) and the like.

(3) Non-steroidal anti-inflammatory drugs Acetaminophen, phenacetin, etenzamide, sulpyrine, antipyrine, migrenin, aspirin, mefenamic acid, flufenamic acid, diclofenac sodium, loxoprofen sodium, phenylbutazone, indomethacin, ibuprofen, ketoprofen, naproxen, oxaprozin , Flurbiprofen, fenbufen, pranoprofen, fructophenine, epirisol, tiaramid hydrochloride, zaltoprofen, gabexate mesylate, camostat mesilate, urinastatin, colchicine, probenade, sulfinpyrazone, benzbromarone, allopurinol, gold sodium thiomalate, Sodium hyaluronate, sodium salicylate, morphine hydrochloride, salicylic acid, Atropine, scopolamine, morphine, pethidine, levorfinol, ketoprofen, naproxen, oxymorphone or a salt thereof.

(4) Steroid drugs Dexamethasone, hexestrol, methimazole, betamethasone, triamcinolone, triamcinolone acetonide, fluocinonide, fluocinolone acetonide, prednisolone, methylprednisolone, cortisone acetate, hydrocortisone, fluorometholone, estriol propionate, etc.

(5) Anticoagulant heparin sodium, sodium citrate, activated protein C, tissue factor pathway inhibitor, antithrombin III, dalteparin sodium, warfarin potassium, argatroban, gabexate, sodium citrate and the like.

(6) Platelet aggregation inhibitor Ozacrel sodium, icosapentarate ethyl, beraprost sodium, alprostadil, ticlopidine hydrochloride, pentoxifylline, dipyridamole and the like.

(7) Thrombolytic drugs Tisokinase, urokinase, streptokinase and the like.

(8) Immunomodulators Cyclosporine, tacrolimus, gusperimus, azathioprine, anti-lymph serum, dry sulfonated immunoglobulin, erythropoietin, colony stimulating factor, interleukin, interferon and the like.

(9) Antiprotozoal drugs Metronidazole, tinidazole, diethylcarbamazine citrate, quinine hydrochloride, quinine sulfate and the like.

(10) Antitussive / Antidepressant Ephedrine hydrochloride, noscapine hydrochloride, codeine phosphate, dihydrocodeine phosphate, isoproterenol hydrochloride, ephedrine hydrochloride, methylephedrine hydrochloride, noscapine hydrochloride, aloclamide, chlorfedianol, picoperidamine, cloperastine, protochlorol , Isoproterenol, salbutamol, tereptaline, oxypetebanol, morphine hydrochloride, dextropetrphan hydrobromide, oxycodone hydrochloride, dimorphan phosphate, tipipedin hibenzate, pentoxyberine citrate, clofedanol hydrochloride, benzonate, guaifenesin, Bromhexine hydrochloride, ambroxol hydrochloride, acetylcysteine, ethylcysteine hydrochloride, carbocysteine, etc.

(11) Sedatives Chlorpromazine hydrochloride, atropine sulfate, phenobarbital, barbital, amobarbital, pentobarbital, thiopental sodium, thiamylal sodium, nitrazepam, estazolam, flurazapam, haloxazolam, triazolam, flunitrazepam, bromvaleryl urea, chloraluril trihydrate Sodium etc.

(12) Anesthetic (12-1) Local anesthetic Cocaine hydrochloride, procaine hydrochloride, lidocaine, dibucaine hydrochloride, tetracaine hydrochloride, mepivacaine hydrochloride, bupivacaine hydrochloride, oxybuprocaine hydrochloride, ethyl aminobenzoate, oxesazein) and the like.
(12-2) General anesthetic <1> Inhalation anesthetic (eg, ether, halothane, nitrous oxide, influrane, enflurane),
<2> Intravenous anesthetics (eg, ketamine hydrochloride, droperidol, thiopental sodium, thiamylal sodium, pentobarbital) and the like.

(13) Anti-ulcer drugs Mecloclopromide, histidine hydrochloride, lansoprazole, metoclopramide, pirenzepine, cimetidine, ranitidine, famotidine, urogastrin, oxesazein, proglumide, omeprazole, sucralfate, sulpiride, cetraxate, gefarnate, aldioxa, teprane .

(14) Arrhythmia drug <1> Sodium channel blocker (eg, quinidine, procainamide, disopyramide, azimarin, lidocaine, mexiletine, phenytoin),
<2> β-blocker (eg, propranolol, alprenolol, bufetrol, oxprenolol, atenol, acebutolol, metoprolol, bisoprolol, pindolol, carteolol, arotinolol),
<3> Potassium channel blocker (eg, amiodarone),
<4> calcium channel blockers (eg, verapamil, diltiazem) and the like.

(15) Antihypertensive diuretic hexamethonium bromide, clonidine hydrochloride, hydrochlorothiazide, trichlormethiazide, furosemide, ethacrynic acid, bumetanide, mefluside, azosemide, spironolactone, potassium canrenoate, triamterene, amiloride, acetazolamide, D-mannitol, isosorbide, aminosorbide Such.

(16) Tranquilizers Diazepam, lorazepam, oxazepam, chlordiazepoxide, medazepam, oxazolam, cloxazolam, clothiazepam, bromazepam, etizolam, fludiazepam, hydroxyzine and the like.

(17) Antipsychotics Chlorpromazine hydrochloride, prochlorperazine, trifluoroperazine, thioridazine hydrochloride, perphenazine maleate, fluphenazine maleate, prochlorperazine maleate, levomepromazine maleate, promethazine hydrochloride, haloperidol, bromoperidol , Spiperone, reserpine, clocapramine hydrochloride, sulpiride, zotepine and the like.

(18) Antitumor agents 6-O- (N-chloroacetylcarbamoyl) fumagillol, bleomycin, methotrexate, actinomycin D, mitomycin C, daunorubicin, adriamycin, neocartinostatin, cytosine arabinoside, fluorouracil, tetrahydrofuryl-5 -Fluorouracil, picibanil, lentinan, levamisole, bestatin, azimexone, glycyrrhizin, doxorubicin hydrochloride, aclarubicin hydrochloride, bleomycin hydrochloride, hepromycin sulfate, vincristine sulfate, vinblastine sulfate, irinotecan hydrochloride, cyclophosphamide, melphalan, busulfan, thiotepa, procarbazine hydrochloride , Cisplatin, azathioprine, mercaptopurine, tegafur, carmofur, cytarabine , Methyl testosterone, testosterone propionate, testosterone enanthate, mepithiostan, phosfestol, chlormadinone acetate, leuprorelin acetate, buserelin acetate.

(19) Antihyperlipidemic drug clofibrate, ethyl 2-chloro-3- [4- (2-methyl-2-phenylpropoxy) phenyl] propionate [Chem. Pharm. Bull), 38, 2792-2796 (1990)], pravastatin, simvastatin, probucol, bezafibrate, clinofibrate, nicomol, cholestyramine, dextran sulfate sodium and the like.

(20) Muscle relaxants Pridinol, tubocurarine, pancuronium, tolperisone hydrochloride, chlorphenesin carbamate, baclofen, chlormezanone, mephenesin, cloxoxazone, eperisone, tizanidine and the like.

(21) Antiepileptic drugs Phenytoin, ethosuximide, acetazolamide, chlordiazepoxide, tripetadione, carbamazepine, phenobarbital, primidone, sultiam, sodium valproate, clonazepam, diazepam, nitrazepam and the like.

(22) antidepressants imipramine, clomipramine, noxiptylline, phenelzine, amitriptyline hydrochloride, nortriptyline hydrochloride, amoxapine, mianserin hydrochloride, maprotiline hydrochloride, sulpiride, fluvoxamine maleate, trazodone hydrochloride, and the like.

(23) Antiallergic drugs diphenhydramine, chlorpheniramine, tripelenamine, methodiramine, clemizole, diphenylpyralin, methoxyphenamine, cromoglycate sodium, tranilast, repirinast, amlexanox, ibudilast, ketotifen, terfenadine, mequitazine, acelastin hydrochloride, epinastine, epinastine hydrochloride Pranlukast hydrate, seratrodast, etc.

(24) Cardiotonic drugs Transbioxocamphor, telephilol, aminophylline, ethylephrine, dopamine, dobutamine, denopamine, aminophylline, vesnarin, amrinone, pimobendan, ubidecarenone, digitoxin, digoxin, methyldigoxin, lanatoside C, G-strophanthin and the like.

(25) Vasodilators Oxyfedrine, diltiazem, tolazoline, hexobenzine, bamethane, clonidine, methyldopa, guanabenz and the like.

(26) Vasoconstricting drugs Dopamine, dobutamine, denopamine and the like.

(27) Antihypertensive diuretics Hexamethonium bromide, pentolinium, mecamylamine, ecarazine, clonidine, diltiazem, nifedipine and the like.

(28) Antidiabetic drugs Tolbutamide, chlorpropamide, acetohexamide, glibenclamide, tolazamide, acarbose, epalrestat, troglitazone, glucagon, grimidine, glipzide, phenformin, buformin, metformin, and the like.

(29) narcotic antagonists such as levalorphan, nalorphine, naloxone or a salt thereof.

(30) Fat-soluble vitamin drugs <1> Vitamin A: Vitamin A ₁ , Vitamin A ₂ and Retinol Palmitate <2> Vitamin D: Vitamin D ₁ , D ₂ , D ₃ , D ₄ and D ₅
<3> Vitamin E: α-tocopherol, β-tocopherol, γ-tocopherol, δ-tocopherol, dl-α-tocopherol nicotinate <4> Vitamin K: vitamins K ₁ , K ₂ , K ₃ and K ₄
<5> Folic acid (vitamin M) and the like.

(31) Vitamin derivatives Various vitamin derivatives, for example, vitamin D ₃ derivatives such as 5,6-trans-cholecalciferol, 2,5-hydroxycholecalciferol, 1-α-hydroxycholecalciferol, 5,6- trans - vitamin D ₂ derivatives such as ergocalciferol.

(32) Anti-asthma drugs Isoprenaline hydrochloride, salbutamol sulfate, procaterol hydrochloride, terbutaline sulfate, trimetoquinol hydrochloride, tulobuterol hydrochloride, orciprenaline sulfate, fenoterol hydrobromide, ephedrine hydrochloride, iprotropium bromide, oxitropium bromide, bromide Flutropium, theophylline, aminophylline, sodium cromoglycate, tranilast, repirinast, amlexanone, ibudilast, ketotifen, terfenadine, mequitazine, azelastine, epinastine, ozagrel hydrochloride, pranlukast hydrate, seratrodast, dexamethasone, prednisolone, hydrocorthion, hydrocorthion Acid beclopetazone and so on.

(33) Frequent urine and urinary incontinence drug Flaboxate hydrochloride and the like.

(34) Atopic dermatitis therapeutic agent, such as sodium cromoglycate.

(35) Allergic rhinitis therapeutic agent Sodium cromoglycate, chlorpheniramine maleate, alimemazine tartrate, clemastine fumarate, homochlorcyclidine hydrochloride, terfenadine, mequitazine and the like.

(36) Pressor drugs Dopamine, dobutamine, denopamine, digitoxin, digoxin, methyldigoxin, lanatoside C, G-strophanthin and the like.

(37) Others Hydroxycam, diatherin, megestrolacetic acid, falselogolin, prostaglandins and the like.

Use of the compound of the present invention or a salt thereof or a prodrug thereof and a concomitant drug has the following effects.
(1) The dose of the compound of the present invention, a salt thereof or a prodrug thereof can be reduced as compared with the case where the compound of the present invention or a salt thereof or a prodrug thereof is administered alone.
(2) A synergistic therapeutic effect can be obtained for diseases such as sepsis, septic shock, inflammatory diseases and infectious diseases.
(3) Exhibits a wide range of therapeutic effects against various diseases that develop with diseases such as bacterial infections.

  When the compound of the present invention or a salt thereof or a prodrug thereof and a concomitant drug are used, the timing of administration of the compound of the present invention or a salt thereof or a prodrug thereof and the concomitant drug is not limited, and the compound of the present invention or a salt thereof or The prodrug and the concomitant drug may be administered simultaneously to the administration subject, or may be administered with a time difference. The dose of the concomitant drug may be determined according to the dose used clinically, and can be appropriately selected depending on the administration subject, administration route, disease, combination and the like.

  The administration mode of the compound of the present invention or a salt thereof or a prodrug thereof and the concomitant drug is not particularly limited, and it is sufficient that the compound of the present invention or a salt thereof or a prodrug thereof and the concomitant drug are combined at the time of administration. Such administration forms vary depending on the type of concomitant drug, etc., but, for example, (1) administration of the composition of the present invention obtained by simultaneously blending the concomitant drug with the compound of the present invention or a salt or prodrug thereof (2) Simultaneous administration of two types of preparations obtained by separately formulating the composition of the present invention and the pharmaceutical composition of the concomitant drug by the same route of administration, and (3) use of the composition of the present invention and the concomitant drug Administration of two types of preparations obtained by separately formulating a pharmaceutical composition with the same administration route with a time difference, (4) Formulating the composition of the present invention and the pharmaceutical composition of a concomitant drug separately Co-administration of two types of preparations obtained by different administration routes, (5) two types of preparations obtained by separately formulating the composition of the present invention and the pharmaceutical composition of the concomitant drug in different administration routes Administration at a time lag (eg the composition of the invention Administration in the order of a pharmaceutical composition of the combination drug, or administration in the reverse order) and the like.

  The pharmaceutical composition of the concomitant drug has low toxicity. For example, the concomitant drug is mixed with a pharmacologically acceptable carrier according to a method known per se, and the pharmaceutical composition such as a tablet (including sugar-coated tablets and film-coated tablets) is mixed. , Powders, granules, capsules (including soft capsules), liquids, injections, suppositories, sustained release, etc., orally or parenterally (eg, topical, rectal, intravenous administration, etc.) be able to. The injection can be administered intravenously, intramuscularly, subcutaneously, or into an organ, or directly to the lesion.

  Examples of pharmacologically acceptable carriers that may be used in the manufacture of a pharmaceutical composition of a concomitant drug include various organic or inorganic carrier substances that are commonly used as pharmaceutical materials. For example, excipients and lubricants in solid formulations Agents, binders and disintegrants, solvents in liquid preparations, solubilizers, suspending agents, tonicity agents, soothing agents and the like. If necessary, additives such as conventional preservatives, antioxidants, colorants, sweeteners, adsorbents, wetting agents and the like can be used in appropriate amounts.

  Examples of the excipient include lactose, sucrose, D-mannitol, starch, corn starch, crystalline cellulose, light anhydrous silicic acid and the like.

  Examples of the lubricant include magnesium stearate, calcium stearate, talc, colloidal silica and the like.

  Examples of the binder include crystalline cellulose, sucrose, D-mannitol, dextrin, hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, starch, sucrose, gelatin, methylcellulose, sodium carboxymethylcellulose and the like.

  Examples of the disintegrant include starch, carboxymethyl cellulose, carboxymethyl cellulose calcium, carboxymethyl starch sodium, L-hydroxypropyl cellulose, and the like.

  Examples of the solvent include water for injection, alcohol, propylene glycol, macrogol, sesame oil, corn oil, olive oil and the like.

  Examples of the solubilizer include polyethylene glycol, propylene glycol, D-mannitol, benzyl benzoate, ethanol, trisaminomethane, cholesterol, triethanolamine, sodium carbonate, sodium citrate and the like.

  Examples of the suspending agent include surfactants such as stearyltriethanolamine, sodium lauryl sulfate, laurylaminopropionic acid, lecithin, benzalkonium chloride, benzethonium chloride, and glyceryl monostearate; for example, polyvinyl alcohol, polyvinylpyrrolidone, carboxy Examples include hydrophilic polymers such as sodium methylcellulose, methylcellulose, hydroxymethylcellulose, hydroxyethylcellulose, and hydroxypropylcellulose.

  Examples of the isotonic agent include glucose, D-sorbitol, sodium chloride, glycerin, D-mannitol and the like.

  Examples of soothing agents include benzyl alcohol.

  Examples of the preservative include p-hydroxybenzoates, chlorobutanol, benzyl alcohol, phenethyl alcohol, dehydroacetic acid, sorbic acid and the like.

  Examples of the antioxidant include sulfite, ascorbic acid, α-tocopherol and the like.

  When a concomitant drug is added to the composition of the present invention, the amount of the concomitant drug can be appropriately selected depending on the administration subject, administration route, disease, etc., but the compound of the present invention or a salt thereof or a prodrug thereof It can adjust similarly to a compounding quantity.

  When the composition of the present invention and the pharmaceutical composition of the concomitant drug are used in combination, the content of the concomitant drug in the pharmaceutical composition of the concomitant drug can be appropriately selected depending on the administration subject, administration route, disease, etc. However, it is usually about 0.01 to 100% by weight, preferably about 0.1 to 50% by weight, more preferably about 0.5 to 20% by weight, based on the whole preparation.

  The content of additives such as carriers in the pharmaceutical composition of the concomitant drug varies depending on the form of the preparation, but is usually about 1 to 99.99% by weight, preferably about 10 to 90% by weight, based on the whole preparation. is there.

  The pharmaceutical composition of the concomitant drug can be produced by a method known per se that is generally used in the preparation process.

  For example, the concomitant drug includes a dispersant (eg, Tween 80 (manufactured by Atlas Powder, USA), HCO 60 (manufactured by Nikko Chemicals), polyethylene glycol, carboxymethylcellulose, sodium alginate, hydroxypropylmethylcellulose, dextrin, etc.) Stabilizers (eg, ascorbic acid, sodium pyrosulfite, etc.), surfactants (eg, polysorbate 80, macrogol, etc.), solubilizers (eg, glycerin, ethanol, etc.), isotonic agents (eg, sodium chloride, Potassium chloride, mannitol, sorbitol, glucose, etc.), pH regulators (eg, hydrochloric acid, sodium hydroxide, etc.), preservatives (eg, ethyl paraoxybenzoate, benzoic acid, methylparaben, propylparaben, benzyl alcohol, etc.), solubilizers (Eg, concentrated glycerin, megurumi Etc.), solubilizing agents (eg, propylene glycol, sucrose, etc.), soothing agents (eg, glucose, benzyl alcohol, etc.), etc., in aqueous injections, or vegetable oils such as olive oil, sesame oil, cottonseed oil, corn oil, propylene It can be dissolved, suspended or emulsified in a solubilizing agent such as glycol, and then molded into an oily injection to obtain an injection.

  Moreover, it can also be set as the emulsion composition for injection of this invention using a concomitant drug instead of the compound of this invention, its salt, or its prodrug.

  The preparation for oral administration is prepared according to a method known per se, such as excipients (eg, lactose, sucrose, starch, etc.), disintegrants (eg, starch, calcium carbonate, etc.), binders (eg, starch, Add gum arabic, carboxymethylcellulose, polyvinylpyrrolidone, hydroxypropylcellulose, etc.) or lubricant (eg, talc, magnesium stearate, polyethylene glycol 6000, etc.), etc. It can be obtained by coating by a method known per se for the purpose of solubility or persistence. Examples of the coating agent include hydroxypropylmethylcellulose, ethylcellulose, hydroxymethylcellulose, hydroxypropylcellulose, polyoxyethylene glycol, Tween 80, Pluronic F68, cellulose acetate phthalate, hydroxypropylmethylcellulose phthalate, hydroxymethylcellulose acetate succinate, Eudragit (Rohm) (Made in Germany, methacrylic acid / acrylic acid copolymer) and dyes (eg, bengara, titanium dioxide, etc.) are used. The preparation for oral administration may be either an immediate release preparation or a sustained release preparation.

  For example, according to a method known per se, the concomitant drug can be made into an oily or aqueous solid, semi-solid or liquid suppository. Examples of the oily base used in the above composition include glycerides of higher fatty acids (eg, cacao butter, witepsols (manufactured by Dynamite Nobel, Germany)), intermediate fatty acids (eg, miglyols (manufactured by Dynamite Nobel, Germany) Etc.], or vegetable oils (eg, sesame oil, soybean oil, cottonseed oil, etc.). Examples of the aqueous base include polyethylene glycols and propylene glycol. Examples of the aqueous gel base include natural gums, cellulose derivatives, vinyl polymers, and acrylic acid polymers.

  Examples of the sustained-release preparation include sustained-release microcapsules.

  In order to obtain a sustained-release type microcapsule, a method known per se can be adopted. For example, it is preferable to form and administer a sustained-release preparation shown in [2] below.

  The concomitant drug can be molded into a preparation for oral administration such as a solid preparation (eg, powder, granule, tablet, capsule) or a preparation for rectal administration such as a suppository, depending on the type of drug. it can.

[1] Combination drug injection and preparation thereof, [2] Concomitant drug sustained release preparation or immediate release preparation and preparation thereof, [3] Concomitant drug sublingual tablet, buccal or intraoral rapid disintegration The agent and its preparation will be specifically described.
[1] Injection and preparation thereof An injection prepared by dissolving a concomitant drug in water is preferable. The injection may contain benzoate and / or salicylate.

  The injection is obtained by dissolving both the concomitant drug and, optionally, benzoate and / or salicylate in water.

  Examples of the salts of benzoic acid and salicylic acid include alkali metal salts such as sodium and potassium, alkaline earth metal salts such as calcium and magnesium, ammonium salts, meglumine salts, and other organic acid salts such as trometamol.

  The concentration of the concomitant drug in the injection is 0.5 to 50 w / v%, preferably about 3 to 20 w / v%. Moreover, the density | concentration of a benzoate or / and a salicylate is 0.5-50 w / v%, Preferably it is 3-20 w / v%.

  In addition, additives generally used in injections such as stabilizers (ascorbic acid, sodium pyrosulfite, etc.), surfactants (polysorbate 80, macrogol, etc.), solubilizers (glycerin, ethanol, etc.) , Isotonic agents (sodium chloride, potassium chloride, etc.), dispersants (hydroxypropylmethylcellulose, dextrin), pH regulators (hydrochloric acid, sodium hydroxide, etc.), preservatives (ethyl paraoxybenzoate, benzoic acid, etc.), dissolution Agents (concentrated glycerin, meglumine, etc.), solubilizing agents (propylene glycol, sucrose, etc.), soothing agents (glucose, benzyl alcohol, etc.) and the like can be appropriately blended. Generally these additives are mix | blended in the ratio normally used for an injection.

  An injection is obtained by dissolving both the concomitant drug and, if desired, benzoate and / or salicylate, and if necessary, the above-mentioned additives in water. These dissolutions may be performed in any order, and can be appropriately performed in the same manner as in the conventional method for producing an injection.

  The aqueous solution for injection is preferably heated, and can be provided as an injection by performing, for example, filtration sterilization, high-pressure heat sterilization, etc., as in the case of ordinary injections.

  The aqueous solution for injection is preferably sterilized by high-pressure heat for 5 to 30 minutes, for example, at 100 to 121 ° C.

  Furthermore, it is good also as a formulation which provided the antibacterial property of the solution so that it could be used as a multidose administration formulation.

[2] Sustained-release preparation or immediate-release preparation and preparation thereof A sustained-release preparation obtained by coating a core containing a concomitant drug with a coating agent such as a water-insoluble substance or a swellable polymer is preferable. For example, a once-daily administration type sustained-release preparation for oral administration is preferred.

  Examples of water-insoluble substances used in the coating agent include cellulose ethers such as ethyl cellulose and butyl cellulose, cellulose esters such as cellulose acetate and cellulose propionate, polyvinyl esters such as polyvinyl acetate and polyvinyl butyrate, acrylic acid / Methacrylic acid copolymer, methyl methacrylate copolymer, ethoxyethyl methacrylate / cinnamoethyl methacrylate / aminoalkyl methacrylate copolymer, polyacrylic acid, polymethacrylic acid, methacrylic acid alkylamide copolymer, poly (methyl methacrylate) , Polymethacrylate, polymethacrylamide, aminoalkyl methacrylate copolymer, poly (methacrylic anhydride), glycidyl methacrylate copolymer, wrinkle Eudragit RS-100, RL-100, RS-30D, RL-30D, RL-PO, RS-PO (ethyl acrylate / methyl methacrylate / ethyl methacrylate / trimethylammonium chloride copolymer), Eudragit NE- Acrylic polymers such as Eudragits (Rohm Pharma) such as 30D (methyl methacrylate / ethyl acrylate copolymer), hardened oils such as hardened castor oil (eg, Lovely Wax (Freund Industries), etc.), Carnauba wax, fatty acid glycerin ester, waxes such as paraffin, polyglycerin fatty acid ester and the like.

  As the swellable polymer, a polymer having an acidic dissociation group and exhibiting pH-dependent swelling is preferable. Swelling is small in an acidic region such as the stomach, and swelling is large in a neutral region such as the small intestine and large intestine. A polymer having an acidic dissociation group is preferred.

  Examples of such a polymer having an acidic dissociable group and exhibiting pH-dependent swelling include, for example, Carbomer 934P, 940, 941, 974P, 980, 1342, polycarbophil, calcium polycarbophil ( Calcium polycarbophil) (all of which are manufactured by BF Goodrich) and Hibiswako 103, 104, 105, 304 (all of which are manufactured by Wako Pure Chemical Industries, Ltd.).

  The film agent used for the sustained release preparation may further contain a hydrophilic substance.

  Examples of the hydrophilic substance include hydroxyalkyl groups or carboxyalkyl groups such as polysaccharides, hydroxypropylcellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose and the like, which may have sulfate groups such as pullulan, dextrin, and alkali metal alginate. Polysaccharide, methylcellulose, polyvinylpyrrolidone, polyvinyl alcohol, polyethylene glycol, and the like.

  The content of the water-insoluble substance in the film of the sustained release preparation is about 30 to about 90% (w / w), preferably about 35 to about 80% (w / w), more preferably about 40 to 75% ( w / w), the swellable polymer content is about 3 to about 30% (w / w), preferably about 3 to about 15% (w / w). The coating agent may further contain a hydrophilic substance, in which case the content of the hydrophilic substance in the coating agent is about 50% (w / w) or less, preferably about 5 to about 40% (w / w), More preferably, it is about 5 to about 35% (w / w). Here, the above% (w / w) represents the weight% with respect to the coating composition obtained by removing the solvent (eg, water, lower alcohol such as methanol, ethanol, etc.) from the coating solution.

  The sustained-release preparation is prepared by preparing a core containing a drug as exemplified below, and then coating the obtained core with a film agent solution in which a water-insoluble substance or a swellable polymer is dissolved by heating or dissolved or dispersed in a solvent. Manufactured by coating.

I. Preparation of the nucleus containing the drug.
The form of the core containing the drug coated with the coating agent (hereinafter sometimes simply referred to as the core) is not particularly limited, but is preferably formed in the form of particles such as granules or fine granules.

  When the nucleus is a granule or a fine particle, the average particle size is preferably about 150 to 2,000 μm, more preferably about 500 to about 1,400 μm.

  The preparation of the nucleus can be carried out by a usual production method. For example, suitable excipients, binders, disintegrants, lubricants, stabilizers and the like are mixed with the drug, and prepared by a wet extrusion granulation method, a fluidized bed granulation method, or the like.

  The drug content of the nucleus is about 0.5 to about 95% (w / w), preferably about 5.0 to about 80% (w / w), more preferably about 30 to about 70% (w / w) It is.

  Examples of excipients contained in the core include saccharides such as sucrose, lactose, mannitol and glucose, starch, crystalline cellulose, calcium phosphate, corn starch and the like. Of these, crystalline cellulose and corn starch are preferable.

  As the binder, for example, polyvinyl alcohol, hydroxypropyl cellulose, polyethylene glycol, polyvinyl pyrrolidone, pluronic F68, gum arabic, gelatin, starch and the like are used. As the disintegrant, for example, carboxymethylcellulose calcium (ECG505), croscarmellose sodium (Ac-Di-Sol), cross-linked polyvinyl pyrrolidone (crospovidone), low substituted hydroxypropylcellulose (L-HPC) and the like are used. Of these, hydroxypropylcellulose, polyvinylpyrrolidone, and low-substituted hydroxypropylcellulose are preferable. For example, talc, magnesium stearate and its inorganic salt are used as a lubricant and an aggregation inhibitor, and polyethylene glycol is used as a lubricant. As the stabilizer, acids such as tartaric acid, citric acid, succinic acid, fumaric acid and maleic acid are used.

  In addition to the production method described above, the nucleus may be prepared by spraying a binder dissolved in an appropriate solvent such as water or a lower alcohol (eg, methanol, ethanol, etc.) It can also be prepared by a rolling granulation method, a pan coating method, a fluidized bed coating method, or a melt granulation method in which a mixture of this and an excipient, a lubricant or the like is added little by little. As the inert carrier particles, for example, those made of sucrose, lactose, starch, crystalline cellulose, waxes can be used, and those having an average particle diameter of about 100 μm to about 1,500 μm are preferable.

  In order to separate the drug contained in the nucleus and the coating agent, the surface of the nucleus may be coated with a protective agent. As the protective agent, for example, the hydrophilic substance, the water-insoluble substance, or the like is used. The protective agent is preferably polyethylene glycol or a polysaccharide having a hydroxyalkyl group or a carboxyalkyl group, more preferably hydroxypropylmethylcellulose or hydroxypropylcellulose. The protective agent may contain as stabilizers acids such as tartaric acid, citric acid, succinic acid, fumaric acid and maleic acid, and lubricants such as talc. When a protective agent is used, the coating amount is about 1 to about 15% (w / w), preferably about 1 to about 10% (w / w), more preferably about 2 to about 8% of the core ( w / w).

  The protective agent can be coated by a normal coating method. Specifically, the protective agent can be coated by spray coating the core by, for example, a fluidized bed coating method, a pan coating method or the like.

II. Coating of the core with a coating agent The core obtained in the above I is coated with a coating agent solution in which the water-insoluble substance, the pH-dependent swelling polymer, and the hydrophilic substance are dissolved by heating or dissolved or dispersed in a solvent. As a result, a sustained-release preparation is produced.

  Examples of the method of coating the core with the coating agent solution include a spray coating method.

  The composition ratio of the water-insoluble substance, the swellable polymer, or the hydrophilic substance in the coating agent solution is appropriately selected so that the content of each component in the film becomes the above-described content.

  The coating amount of the coating agent is about 1 to about 90% (w / w), preferably about 5 to about 50% (w / w) with respect to the core (excluding the coating amount of the protective agent), more preferably About 5 to 35% (w / w).

  As the solvent of the film agent solution, water or an organic solvent can be used alone or a mixture of the two can be used. The mixing ratio of water and organic solvent (water / organic solvent: weight ratio) in the case of using the mixed liquid can be varied in the range of 1 to 100%, preferably 1 to about 30%. The organic solvent is not particularly limited as long as it dissolves water-insoluble substances. For example, lower alcohols such as methyl alcohol, ethyl alcohol, isopropyl alcohol and n-butyl alcohol, lower alkanones such as acetone, acetonitrile, chloroform, Methylene chloride or the like is used. Of these, lower alcohols are preferred, and ethyl alcohol and isopropyl alcohol are particularly preferred. Water and a mixed solution of water and an organic solvent are preferably used as the solvent for the film agent. At this time, if necessary, an acid such as tartaric acid, citric acid, succinic acid, fumaric acid, and maleic acid may be added to the coating agent solution for stabilizing the coating agent solution.

  The operation in the case of coating by spray coating can be carried out by a usual coating method, specifically, by carrying out spray coating of a film agent solution on the core by, for example, fluidized bed coating method, pan coating method, etc. Can do. If necessary, plasticize glycerin fatty acid ester, hydrogenated castor oil, triethyl citrate, cetyl alcohol, stearyl alcohol, etc., using talc, titanium oxide, magnesium stearate, calcium stearate, light anhydrous silicic acid as lubricant. You may add as an agent.

  After coating with a coating agent, an antistatic agent such as talc may be mixed as necessary.

  The immediate release preparation may be liquid (solution, suspension, emulsion, etc.) or solid (particle, pill, tablet, etc.). Oral administration agents and parenteral administration agents such as injections are used, and oral administration agents are preferred.

  The immediate-release preparation usually contains a carrier, an additive or an excipient (hereinafter sometimes abbreviated as an excipient) commonly used in the pharmaceutical field in addition to the drug as the active ingredient. . The formulation excipient used is not particularly limited as long as it is an excipient commonly used as a formulation excipient. For example, excipients for oral solid preparations include lactose, starch, corn starch, crystalline cellulose (Asahi Kasei Co., Ltd., Avicel PH101, etc.), powdered sugar, granulated sugar, mannitol, light anhydrous silicic acid, magnesium carbonate, calcium carbonate , L-cysteine and the like, preferably corn starch and mannitol. These excipients can be used alone or in combination of two or more. The content of the excipient is, for example, about 4.5 to about 99.4 w / w%, preferably about 20 to about 98.5 w / w%, more preferably about 30 to about 9%, based on the total amount of the immediate-release preparation. 97 w / w%.

  The content of the drug in the immediate release preparation can be appropriately selected from the range of about 0.5 to about 95%, preferably about 1 to about 60%, based on the total amount of the immediate release preparation.

  When the immediate-release preparation is an oral solid preparation, it usually contains a disintegrant in addition to the above components. Examples of such disintegrants include carboxymethyl cellulose calcium (manufactured by Gotoku Pharmaceutical Co., ECG-505), croscarmellose sodium (eg, Asahi Kasei Co., Ltd., Akizol), crospovidone (eg, BASF Co., Ltd., Kollidon CL). , Low-substituted hydroxypropyl cellulose (Shin-Etsu Chemical Co., Ltd.), carboxymethyl starch (Matsutani Chemical Co., Ltd.), sodium carboxymethyl starch (manufactured by Kimura Sangyo Co., Ltd., Proprotab), partially pregelatinized starch (manufactured by Asahi Kasei Co., Ltd.) , PCS), etc. can be used. For example, a substance that disintegrates granules by contacting with water, absorbing water, swelling, or forming a channel between the active ingredient constituting the core and the excipient can be used. . These disintegrants can be used alone or in combination of two or more. The amount of the disintegrant is appropriately selected depending on the type and amount of the concomitant drug to be used, the design of the releasable preparation, etc., but for example, about 0.05 to about 30 w / w%, Preferably, it is about 0.5 to about 15 w / w%.

  When the immediate-release preparation is an oral solid preparation, in the case of an oral solid preparation, an additive commonly used in the solid preparation may further be included, if desired, in addition to the above composition. Examples of such additives include binders (for example, sucrose, gelatin, gum arabic powder, methylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, carboxymethylcellulose, polyvinylpyrrolidone, pullulan, and dextrin), lubricants (for example, , Polyethylene glycol, magnesium stearate, talc, light anhydrous silicic acid (eg, Aerosil (Nippon Aerosil)), surfactants (eg, anionic surfactants such as sodium alkyl sulfate, polyoxyethylene fatty acid esters and polyoxyethylene) Sorbitan fatty acid esters, nonionic surfactants such as polyoxyethylene castor oil derivatives), colorants (eg tar dyes, caramel, bengara, titanium oxide, riboflavins), If necessary, bridging agents (for example, sweeteners, fragrances, etc.), adsorbents, preservatives, wetting agents, antistatic agents, etc. are used, and tartaric acid, citric acid, succinic acid, fumaric acid are used as stabilizers. Organic acids such as may be added.

  As the binder, hydroxypropylcellulose, polyethylene glycol, polyvinylpyrrolidone and the like are preferably used.

  The immediate-release preparation can be prepared by mixing the above-described components, further kneading, if necessary, and molding based on a normal preparation manufacturing technique. The mixing is performed by a generally used method such as mixing and kneading. Specifically, for example, when an immediate-release preparation is formed in a particulate form, a vertical granulator, a universal kneader (manufactured by Hata Iron Works), fluidized by the same method as the core preparation method of the sustained-release preparation It can be prepared by mixing using a layer granulator FD-5S (manufactured by POWREC) or the like and then granulating by a wet extrusion granulation method, a fluidized bed granulation method or the like.

  The immediate-release preparation and the sustained-release preparation thus obtained are administered as they are or as appropriate, together with preparation excipients, etc., separately according to a conventional method, and then simultaneously or in combination with an arbitrary administration interval. Alternatively, both of them may be formulated into one orally administered preparation (eg, granules, fine granules, tablets, capsules, etc.) together with preparation excipients or the like as they are or as appropriate. Both preparations may be made into granules or fine granules and filled in the same capsule or the like for preparation for oral administration.

[3] Sublingual tablet, buccal or intraoral quick disintegrating agent and preparation thereof The sublingual tablet, buccal preparation and intraoral quick disintegrating agent may be a solid preparation such as a tablet, or an oral mucosa patch (film). There may be.

  As the sublingual tablet, buccal or intraoral quick disintegrating agent, a preparation containing a concomitant drug and an excipient is preferable. Further, it may contain auxiliary agents such as a lubricant, an isotonic agent, a hydrophilic carrier, a water-dispersible polymer, and a stabilizer. Further, β-cyclodextrin or β-cyclodextrin derivatives (eg, hydroxypropyl-β-cyclodextrin, etc.) may be contained in order to facilitate absorption and increase bioavailability.

  Examples of the excipient include lactose, sucrose, D-mannitol, starch, crystalline cellulose, and light anhydrous silicic acid. Examples of the lubricant include magnesium stearate, calcium stearate, talc, colloidal silica and the like, and magnesium stearate and colloidal silica are particularly preferable. Examples of the isotonic agent include sodium chloride, glucose, fructose, mannitol, sorbitol, lactose, saccharose, glycerin, urea and the like, and mannitol is particularly preferable. Examples of hydrophilic carriers include swellable hydrophilic carriers such as crystalline cellulose, ethyl cellulose, crosslinkable polyvinyl pyrrolidone, light anhydrous silicic acid, silicic acid, dicalcium phosphate, calcium carbonate, and particularly crystalline cellulose (eg, microcrystalline cellulose). Is preferred. Water-dispersible polymers include gums (eg, tragacanth gum, acacia gum, guar gum), alginates (eg, sodium alginate), cellulose derivatives (eg, methylcellulose, carboxymethylcellulose, hydroxymethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose), gelatin , Water-soluble starch, polyacrylic acid (eg, carbomer), polymethacrylic acid, polyvinyl alcohol, polyethylene glycol, polyvinylpyrrolidone, polycarbophil, ascorbate, palmitate, etc., hydroxypropyl methylcellulose, polyacrylic acid, Alginate, gelatin, carboxymethylcellulose, polyvinylpyrrolidone, polyethylene glycol and the like are preferable. Hydroxypropyl methylcellulose is particularly preferable. Examples of the stabilizer include cysteine, thiosorbitol, tartaric acid, citric acid, sodium carbonate, ascorbic acid, glycine, sodium sulfite and the like, and citric acid and ascorbic acid are particularly preferable.

  The sublingual tablet, buccal or intraoral quick disintegrating agent can be produced by mixing the concomitant drug and the excipient by a method known per se. Furthermore, auxiliary agents such as the above-mentioned lubricants, tonicity agents, hydrophilic carriers, water-dispersible polymers, stabilizers, colorants, sweeteners, preservatives and the like may be mixed as desired. After mixing the above components simultaneously or with a time difference, a sublingual tablet, a buccal tablet or an intraoral quick disintegrating tablet is obtained by compression tableting. In order to obtain an appropriate hardness, it may be produced by moistening / wetting with a solvent such as water or alcohol as necessary before and after the tableting molding process, and drying after molding.

  In the case of molding into a mucous membrane adhesive tablet (film), a solution obtained by dissolving the concomitant drug and the above-mentioned water-dispersible polymer (preferably hydroxypropylcellulose, hydroxypropylmethylcellulose), excipients, etc. in a solvent such as water. Is cast into a film. Furthermore, additives such as a plasticizer, a stabilizer, an antioxidant, a preservative, a coloring agent, and a sweetener may be added. Contains glycols such as polyethylene glycol and propylene glycol to give the film proper elasticity, and contains bioadhesive polymers (eg, polycarbophil, carbopol) to enhance film adhesion to the mucosal lining of the oral cavity You may let them. Casting is performed by pouring the solution onto a non-adhesive surface, spreading it to a uniform thickness (preferably about 10 to 1000 microns) with an application tool such as a doctor blade, and then drying the solution to form a film. Achieved. The film thus formed may be dried at room temperature or under heating and cut to a desired surface area.

  Preferable intraoral quick disintegrating agent includes a solid rapid diffusion agent comprising a network of a concomitant drug and a water-soluble or water-diffusible carrier that is inactive with the concomitant drug. The network is obtained by evaporating the solvent from a solid composition composed of a solution obtained by dissolving the concomitant drug in an appropriate solvent and the carrier.

  In addition to the concomitant drug, the composition of the intraoral quick disintegrating agent preferably contains a matrix forming agent and a secondary component.

  Examples of the matrix-forming agent include gelatins, dextrins, and animal or vegetable proteins such as soybean, wheat and psyllium seed proteins; gums such as gum arabic, gar gum, agar and xanthan; polysaccharides Carboxymethylcelluloses; carrageenans; dextrans; pectins; synthetic polymers such as polyvinylpyrrolidone; materials derived from gelatin-gum arabic complex and the like. Furthermore, saccharides such as mannitol, dextrose, lactose, galactose and trehalose; cyclic saccharides such as cyclodextrin; inorganic salts such as sodium phosphate, sodium chloride and aluminum silicate; glycine, L-alanine, L-aspartic acid, L- Examples include amino acids having 2 to 12 carbon atoms such as glutamic acid, L-hydroxycycloline, L-isoleucine, L-leucine and L-phenylalanine.

  One or more of the matrix forming agents can be introduced into a solution or suspension before solidification. Such a matrix forming agent may be present in addition to the surfactant, or may be present with the surfactant excluded. In addition to forming the matrix, the matrix-forming agent can help maintain the diffusion state of the compound of the invention or the concomitant drug in the solution or suspension.

  Secondary components such as preservatives, antioxidants, surfactants, thickeners, colorants, pH adjusters, flavoring agents, sweeteners or taste masking agents may be included in the composition. Suitable colorants include red, black and yellow iron oxides and FD & C dyes such as FD & C Blue 2 and FD & C Red 40 from Ellis & Everard. Suitable flavorings include mint, raspberry, licorice, orange, lemon, grapefruit, caramel, vanilla, cherry and grape flavor and combinations thereof. Suitable pH adjusting agents include citric acid, tartaric acid, phosphoric acid, hydrochloric acid and maleic acid. Suitable sweeteners include aspartame, acesulfame K and thaumatin. Suitable taste masking agents include sodium bicarbonate, ion exchange resins, cyclodextrin inclusion compounds, adsorbate materials, and microencapsulated apomorphine.

  The formulation usually contains about 0.1 to about 50% by weight, preferably about 0.1 to about 30% by weight of the concomitant drug, between about 1 minute to about 60 minutes, preferably about 1 minute to about 15 minutes. Or more preferably about 2 minutes to about 5 minutes (in water) that can dissolve 90% or more of the concomitant drug (above, sublingual tablets, buccals, etc.) or placed in the oral cavity The intraoral fast disintegrating agent that disintegrates within 1 to 60 seconds, preferably within 1 to 30 seconds, more preferably within 1 to 10 seconds is preferable.

  The content of the excipient in the whole preparation is about 10 to about 99% by weight, preferably about 30 to about 90% by weight. The content of β-cyclodextrin or β-cyclodextrin derivative in the whole preparation is 0 to about 30% by weight. The content of the lubricant in the whole preparation is about 0.01 to about 10% by weight, preferably about 1 to about 5% by weight. The content of the tonicity agent in the whole preparation is about 0.1 to about 90% by weight, preferably about 10 to about 70% by weight. The content of the hydrophilic carrier in the whole preparation is about 0.1 to about 50% by weight, preferably about 10 to about 30% by weight. The content of the water-dispersible polymer in the whole preparation is about 0.1 to about 30% by weight, preferably about 10 to about 25% by weight. The content of the stabilizer in the whole preparation is about 0.1 to about 10% by weight, preferably about 1 to about 5% by weight. The preparation may further contain additives such as colorants, sweeteners, preservatives and the like as necessary.

  The dose of the pharmaceutical composition of the concomitant drug varies depending on the type of concomitant drug, age, body weight, symptom, dosage form, administration method, administration period, etc., for example, per patient (adult, body weight approximately 60 kg) per person, As a concomitant drug, about 0.01 to about 1000 mg / kg per day, preferably about 0.01 to about 100 mg / kg, more preferably about 0.1 to about 100 mg / kg, especially about 0.1 to about 50 mg / Kg, in particular, about 1.5 to about 30 mg / kg is administered intravenously in portions from once to several times a day. Of course, as described above, the dosage varies depending on various conditions. Therefore, a dosage smaller than the dosage may be sufficient, or the dosage may need to be administered beyond the range.

  The amount of the concomitant drug can be set as long as side effects do not become a problem. The daily dose as a concomitant drug varies depending on the degree of symptoms, age of the subject, sex, weight, sensitivity difference, timing of administration, interval, nature of the pharmaceutical preparation, formulation, type, type of active ingredient, etc. Although it is not limited, the amount of the drug is usually about 0.001 to 2000 mg, preferably about 0.01 to 500 mg, more preferably about 0.1 to 100 mg per kg body weight of the mammal by oral administration, Is usually divided into 1 to 4 times a day.

  When the composition of the present invention and the pharmaceutical composition of the concomitant drug are administered in combination, they may be administered at the same time, but after the pharmaceutical composition of the concomitant drug is administered first, the composition of the present invention is The composition of the present invention may be administered first, followed by the pharmaceutical composition of the concomitant drug. When administered at a time difference, the time difference varies depending on the active ingredient to be administered, dosage form, and administration method. For example, when administering the pharmaceutical composition of the concomitant drug first, after administering the pharmaceutical composition of the concomitant drug, 1 Examples include a method of administering the composition of the present invention within minutes to 3 days, preferably within 10 minutes to 1 day, more preferably within 15 minutes to 1 hour. When the composition of the present invention is administered first, after the composition of the present invention is administered, the concomitant drug is administered within 1 minute to 1 day, preferably within 10 minutes to 6 hours, more preferably within 15 minutes to 1 hour. The method of administering a pharmaceutical composition is mentioned.

  Next, reference examples, examples and comparative examples will be described to describe the present invention in more detail. In addition, the following examples etc. illustrate the present invention and do not limit the present invention thereto.

^{The 1} H-NMR spectrum was measured with a Varian Gemini 200 (200 MHz) spectrometer using tetramethylsilane as an internal standard, and all δ values were shown in ppm. In the mixed solvent, the numerical value shown in parentheses is the volume mixing ratio of each solvent. % Means weight percent unless otherwise specified. The solvent ratio in silica gel chromatography indicates the volume ratio of the solvent to be mixed.

  A highly polar diastereomer is a diastere having a smaller Rf value when comparing Rf values of normal phase thin layer chromatography under the same conditions (for example, ethyl acetate / hexane can be used as a solvent). A stereomer is meant, and a low-polar diastereomer means a diastereomer having a larger Rf value.

Each symbol in the examples has the following meaning.
s: singlet, d: doublet, t: triplet, q: quartet, dd: double doublet, tt: triple triplet, m: multiplet, br: wide, J: coupling constant

  The following Reference Example A can be produced according to the reference example of WO99 / 4622, and Reference Example B can be produced according to the example of WO99 / 46242.

[Reference Example A]
Reference Example A1 Ethyl 2-sulfo-1-cyclohexene-1-carboxylate Reference Example A2 Ethyl 2-chlorosulfonyl-1-cyclohexene-1-carboxylate Reference Example A3 Ethyl 2-chlorosulfonyl-1-cyclopentene-1-carboxylate Reference Example A4 Ethyl 2-Chlorosulfonyl-1-cycloheptene-1-carboxylate Reference Example A5 6- [N- (4-Chloro-2-fluorophenyl) sulfamoyl] -1-cyclohexene-1-carboxylic acid sodium salt Reference Example A6 1- (3-Fluoro-4-nitrophenyl) -1H-1,2,4-triazole reference example A7 1- (4-amino-3-fluorophenyl) -1H-1,2,4-triazole reference example A8 Methyl 4-benzyloxycarbonylamino-3-chlorobenzoate Steal reference example A9 4-benzyloxycarbonylamino-3-chlorobenzoic acid reference example A10 tert-butyl N- (4-benzyloxycarbonylamino-3-chlorobenzoyl) glycinate reference example A11 tert-butyl N- (4-amino -3-Chlorobenzoyl) glycinate Reference Example A12 6- [N- (2,4-difluorophenyl) sulfamoyl] -1-cyclohexene-1-carboxylic acid Reference Example A13 Ethyl 2-mercapto-5-phenyl-1-cyclohexene- 1-carboxylate reference example A14 ethyl 2-chlorosulfonyl-5-phenyl-1-cyclohexene-1-carboxylate reference example A15 ethyl 5-tert-butyl-2-mercapto-1-cyclohexene-1-carboxylate reference example A16 Ethyl 5 tert-Butyl-2-chlorosulfonyl-1-cyclohexene-1-carboxylate Reference Example A17 Ethyl 5,5-dimethyl-2-mercapto-1-cyclohexene-1-carboxylate Reference Example A18 Ethyl 2-chlorosulfonyl-5 5-Dimethyl-1-cyclohexene-1-carboxylate

[Reference Example B]
Reference Example B1 Ethyl 6- [N- (4-chloro-2-fluorophenyl) sulfamoyl] -1-cyclohexene-1-carboxylate (Compound 1)
Reference Example B2 Ethyl 6- [N- (4-chloro-2-fluorophenyl) -N-methylsulfamoyl] -1-cyclohexene-1-carboxylate (Compound 2)
Reference Example B3 Ethyl 6- [N- (2,4-difluorophenyl) sulfamoyl] -1-cyclohexene-1-carboxylate (Compound 3)
Reference Example B4 Ethyl 6- [N- (2,6-diisopropylphenyl) sulfamoyl] -1-cyclohexene-1-carboxylate (Compound 4)
Reference Example B5 Ethyl 6- [N- (4-nitrophenyl) sulfamoyl] -1-cyclohexene-1-carboxylate (Compound 5)
Reference Example B6 Ethyl 6- (N-phenylsulfamoyl) -1-cyclohexene-1-carboxylate (Compound 6)
Ethyl 2- (N-phenylsulfamoyl) -1-cyclohexene-1-carboxylate (Compound 7)
Reference Example B7 Ethyl 2- [N- (4-chloro-2-fluorophenyl) sulfamoyl] -1-cyclohexene-1-carboxylate (Compound 9)
Reference Example B8 2- (4-methoxyphenyl) -4,5,6,7-tetrahydro-1,2-benzisothiazol-3 (2H) -one 1,1-dioxide (Compound 67)
Ethyl 2- [N- (4-methoxyphenyl) sulfamoyl] -1-cyclohexene-1-carboxylate (Compound 8)
Reference Example B9 Ethyl 6- [N- (2-fluorophenyl) sulfamoyl] -1-cyclohexene-1-carboxylate (Compound 10)
Reference Example B10 Ethyl 6- [N- (3-fluorophenyl) sulfamoyl] -1-cyclohexene-1-carboxylate (Compound 11)
Reference Example B11 2- (4-Fluorophenyl) -4,5,6,7-tetrahydro-1,2-benzisothiazol-3 (2H) -one-1,1-dioxide (Compound 68)
Ethyl 6- [N- (4-fluorophenyl) sulfamoyl] -1-cyclohexene-1-carboxylate (Compound 12)
Ethyl 2- [N- (4-fluorophenyl) sulfamoyl] -1-cyclohexene-1-carboxylate (Compound 18)
Reference Example B12 Ethyl 6- [N- (2,6-difluorophenyl) sulfamoyl] -1-cyclohexene-1-carboxylate (Compound 13)
Reference Example B13 Ethyl 6- [N- (2,3-difluorophenyl) sulfamoyl] -1-cyclohexene-1-carboxylate (Compound 14)
Reference Example B14 Ethyl 6- [N- (2,5-difluorophenyl) sulfamoyl] -1-cyclohexene-1-carboxylate (Compound 15)
Reference Example B15 Ethyl 6- [N- (3,4-difluorophenyl) sulfamoyl] -1-cyclohexene-1-carboxylate (Compound 16)
Reference Example B16 Ethyl 6- [N- (3,5-difluorophenyl) sulfamoyl] -1-cyclohexene-1-carboxylate (Compound 17)
Reference Example B17 l-ethyl 6- [N- (2,4-difluorophenyl) sulfamoyl] -1-cyclohexene-1-carboxylate (Compound 19)
d-ethyl 6- [N- (2,4-difluorophenyl) sulfamoyl] -1-cyclohexene-1-carboxylate (d-ethyl 6- [N- (2,4-difluorophenyl) sulfamoyl] cyclohex-1- Ene-1-carboxylate) (compound 20)
Reference Example B18 Ethyl 6- [N- (2-ethoxycarbonylphenyl) sulfamoyl] -1-cyclohexene-1-carboxylate (Compound 21)
Reference Example B19 Methyl 6- [N- (2,4-difluorophenyl) sulfamoyl] -1-cyclohexene-1-carboxylate (Compound 22)
Reference Example B20 Propyl 6- [N- (2,4-difluorophenyl) sulfamoyl] -1-cyclohexene-1-carboxylate (Compound 23)
Reference Example B21 Methyl 6- [N- (4-chloro-2-fluorophenyl) sulfamoyl] -1-cyclohexene-1-carboxylate (Compound 24)
Reference Example B22 Isopropyl 6- [N- (2,4-difluorophenyl) sulfamoyl] -1-cyclohexene-1-carboxylate (Compound 25)
Reference Example B23 Ethyl 6- [N- (2-methoxycarbonylphenyl) sulfamoyl] -1-cyclohexene-1-carboxylate (Compound 26)
Reference Example B24 Ethyl 6- [N- (2-fluoro-4-methylphenyl) sulfamoyl] -1-cyclohexene-1-carboxylate (Compound 27)
Reference Example B25 Ethyl 6- [N- (2-chlorophenyl) sulfamoyl] -1-cyclohexene-1-carboxylate (ethyl 6- [N- (2-chlorophenyl) sulfamoyl] cyclohex-1-ene-1-carboxylate) (Compound 28)
Reference Example B26 Ethyl 6- [N- (2-chloro-4-fluorophenyl) sulfamoyl] -1-cyclohexene-1-carboxylate (Compound 29)
Reference Example B27 Ethyl 6- [N- (4-chlorophenyl) sulfamoyl] -1-cyclohexene-1-carboxylate (Compound 30)
Reference Example B28 Ethyl 6- [N- (2,3,4-trifluorophenyl) sulfamoyl] -1-cyclohexene-1-carboxylate (Compound 31)
Reference Example B29 Isobutyl 6- [N- (2,4-difluorophenyl) sulfamoyl] -1-cyclohexene-1-carboxylate (Compound 32)
Reference Example B30 Butyl 6- [N- (2,4-difluorophenyl) sulfamoyl] -1-cyclohexene-1-carboxylate (Compound 33)
Reference Example B31 Ethyl 6- [N- (4-bromo-2-fluorophenyl) sulfamoyl] -1-cyclohexene-1-carboxylate (Compound 34)
Reference Example B32 Ethyl 6- [N- (2,4-dichlorophenyl) sulfamoyl] -1-cyclohexene-1-carboxylate (Compound 35)
Reference Example B33 Ethyl 6- [N- (2-acetoxyphenyl) sulfamoyl] -1-cyclohexene-1-carboxylate (Compound 36)
Reference Example B34 Ethyl 6- [N- (3-chlorophenyl) sulfamoyl] -1-cyclohexene-1-carboxylate (Compound 37)
Reference Example B35 Ethyl 6- [N- (2,3-dichlorophenyl) sulfamoyl] -1-cyclohexene-1-carboxylate (Compound 38)
Reference Example B36 Ethyl 6- [N- (2-ethylphenyl) sulfamoyl] -1-cyclohexene-1-carboxylate (Compound 39)
Reference Example B37 Ethyl 6- [N- [4- (2H-1,2,3-triazol-2-yl) phenyl] sulfamoyl] -1-cyclohexene-1-carboxylate (Compound 40)
Reference Example B38 Ethyl 6- [N- (2,5-dichlorophenyl) sulfamoyl] -1-cyclohexene-1-carboxylate (Compound 41)
Reference Example B39 Ethyl 6- [N- (2-trifluoromethoxyphenyl) sulfamoyl] -1-cyclohexene-1-carboxylate (Compound 42)
Reference Example B40 Ethyl 6- [N- (2,4,5-trifluorophenyl) sulfamoyl] -1-cyclohexene-1-carboxylate (Compound 43)
Reference Example B41 Ethyl 6- [N- [4- (2H-tetrazol-2-yl) phenyl] sulfamoyl] -1-cyclohexene-1-carboxylate (Compound 44)
Reference Example B42 Ethyl 6- [N- (2-chloro-4-methylphenyl) sulfamoyl] -1-cyclohexene-1-carboxylate (ethyl 6- [N- (2-chloro-4-methylphenyl) sulfamoyl] cyclohexa -1-ene-1-carboxylate) (Compound 45)
Reference Example B43 Ethyl 6- [N- (4-fluoro-2-methylphenyl) sulfamoyl] -1-cyclohexene-1-carboxylate (Compound 46)
Reference Example B44 Ethyl 6- [N- (2,6-dichlorophenyl) sulfamoyl] -1-cyclohexene-1-carboxylate (Compound 47)
Reference Example B45 Ethyl 6- [N- [4- (1H-tetrazol-1-yl) phenyl] sulfamoyl] -1-cyclohexene-1-carboxylate (Compound 48)
Reference Example B46 Ethyl 6- [N- (4- (1H-1,2,3-triazol-1-yl) phenyl] sulfamoyl] -1-cyclohexene-1-carboxylate (Compound 49)
Reference Example B47 Ethyl 6- [N- (2-trifluoromethylphenyl) sulfamoyl] -1-cyclohexene-1-carboxylate (Compound 50)
Reference Example B48 Ethyl 6- [N- (4-methoxycarbonylphenyl) sulfamoyl] -1-cyclohexene-1-carboxylate (Compound 51)
Reference Example B49 benzyl 6- [N- (2,4-difluorophenyl) sulfamoyl] -1-cyclohexene-1-carboxylate (Compound 52)
Reference Example B50 Ethyl 6- [N- [4- [2,3-bis (tert-butoxycarbonyl) guanidinomethyl] phenyl] sulfamoyl] -1-cyclohexene-1-carboxylate (Compound 53)
Reference Example B51 Ethyl 6- [N- (2-chloro-4-methoxycarbonylphenyl) sulfamoyl] -1-cyclohexene-1-carboxylate (Compound 54)
Reference Example B52 Ethyl 6- [N- (2-chloro-4-cyanophenyl) sulfamoyl] -1-cyclohexene-1-carboxylate (Compound 55)
Reference Example B53 2-hydroxyethyl 6- [N- (2,4-difluorophenyl) sulfamoyl] -1-cyclohexene-1-carboxylate (Compound 56)
Reference Example B54 Ethyl 6- [N- [2-fluoro-4- (1H-1,2,4-triazol-1-yl) phenyl] sulfamoyl] -1-cyclohexene-1-carboxylate (Compound 57)
Reference Example B55 Ethyl 2- [N- (2,4-difluorophenyl) sulfamoyl] -1-cyclopentene-1-carboxylate (Compound 66)
Ethyl 5- [N- (2,4-difluorophenyl) sulfamoyl] -1-cyclopentene-1-carboxylate (Compound 58)
Reference Example B56 tert-butyl [6- [N- (2,4-difluorophenyl) sulfamoyl] -1-cyclohexen-1-yl] carbonyloxyacetate (Compound 59)
Reference Example B57 [6- [N- (2,4-difluorophenyl) sulfamoyl] -1-cyclohexen-1-yl] carbonyloxyacetic acid (Compound 60)
Reference Example B58 Ethyl 7- [N- (2,4-difluorophenyl) sulfamoyl] -1-cycloheptene-1-carboxylate (Compound 61)
Reference Example B59 Ethyl 6- [N- [2-chloro-4- (N-tert-butoxycarbonylmethylcarbamoyl) phenyl] sulfamoyl] -1-cyclohexene-1-carboxylate (Compound 62)
Reference Example B60 Ethyl 6- [N- [2-chloro-4- (N-ethoxycarbonylmethylcarbamoyl) phenyl] sulfamoyl] -1-cyclohexene-1-carboxylate (Compound 63)
Reference Example B61 Ethyl 5- [N- (2-chloro-4-fluorophenyl) sulfamoyl] -1-cyclopentene-1-carboxylate (Compound 64)
Reference Example B62 2- [4- (2,2,3,3,3-pentafluoropropoxy) phenyl] -4,5,6,7-tetrahydro-1,2-benzisothiazol-3 (2H) -one 1,1-dioxide (Compound 69)
Reference Example B63 Ethyl 7- [N- (2-chloro-4-fluorophenyl) sulfamoyl] -1-cycloheptene-1-carboxylate (Compound 65)
Reference Example B64 2- (2,4-difluorophenyl) -5,6,7,7a-tetrahydro-1,2-benzisothiazol-3 (2H) -one 1,1-dioxide (Compound 70)
Reference Example B65 Ethyl 6- [N- (2-chloro-4-fluorophenyl) sulfamoyl] -1-cyclohexene-1-carboxylate (Compound 29)
Reference Example B66 l-ethyl 6- [N- (2-chloro-4-fluorophenyl) sulfamoyl] -1-cyclohexene-1-carboxylate (Compound 71)
d-ethyl 6- [N- (2-chloro-4-fluorophenyl) sulfamoyl] -1-cyclohexene-1-carboxylate (ethyl (6R) -6- [N- (2-chloro-4-fluorophenyl) Sulfamoyl] cyclohex-1-ene-1-carboxylate) (compound 72)
Reference Example B67 Ethyl 6- [N- (2-bromo-4-fluorophenyl) sulfamoyl] -1-cyclohexene-1-carboxylate (Compound 73)
Reference Example B68 Ethyl 6- [N- (4-bromo-2-chlorophenyl) sulfamoyl] -1-cyclohexene-1-carboxylate (Compound 74)
Reference Example B69 High Polarity Diastereomer (Compound 75) and Low Polarity Diastereomer (Compound) of ethyl 6- [N- (2,4-difluorophenyl) sulfamoyl] -3-phenyl-1-cyclohexene-1-carboxylate 76)
Reference Example B70 High Polar Diastereomer (Compound 77) and Low Polar Diastereomer of Ethyl 6- [N- (2-Chloro-4-fluorophenyl) sulfamoyl] -3-phenyl-1-cyclohexene-1-carboxylate (Compound 78)
Reference Example B71 High polar diastereomer (Compound 79) and low polar diastereomer of ethyl 6- [N- (2,4-difluorophenyl) sulfamoyl] -3-tert-butyl-1-cyclohexene-1-carboxylate (Compound 80)
Reference Example B72 High Polarity Diastereomer (Compound 81) and Low Polarity Dia of Ethyl 6- [N- (2-chloro-4-fluorophenyl) sulfamoyl] -3-tert-butyl-1-cyclohexene-1-carboxylate Stereomer (Compound 82)
Reference Example B73 Ethyl 6- [N- (2,4-difluorophenyl) sulfamoyl] -3,3-dimethyl-1-cyclohexene-1-carboxylate (Compound 83)
Reference Example B74 Ethyl 6- [N- (2-chloro-4-fluorophenyl) sulfamoyl] -3,3-dimethyl-1-cyclohexene-1-carboxylate (Compound 84)
Reference Example B75 Ethyl 3-bromo-6- [N- (2,4-difluorophenyl) sulfamoyl] -1-cyclohexene-1-carboxylate (Compound 85)
Specific examples are shown in Tables 1 to 5.

  Reference Example C below can be prepared according to the reference example of WO01 / 10826, and Reference Example D can be prepared according to the example of WO01 / 10826.

[Reference Example C]
Reference example C1
Ethyl 6- [N- (2,4-difluorophenyl) sulfamoyl] -1-cyclohexene-1-carboxylate (1 g, synthesized by the method described in Japanese Patent Application No. 10-056492) and phenylmethanethiol (719 mg) 1,8-Diazabicyclo [5,4,0] -7-undecene (441 mg) was added dropwise to an N, N-dimethylformamide (20 ml) solution under ice cooling, and the mixture was stirred at room temperature for 18 hours. The reaction mixture was diluted with ethyl acetate (100 ml), washed with water (70 ml × 2) and saturated brine (70 ml), and dried over anhydrous sodium sulfate. The residue obtained by distilling off the solvent was purified by flash silica gel column chromatography (eluent: toluene) to obtain ethyl 6- (benzylsulfanyl) -1-cyclohexene-1-carboxylate (673 mg). Obtained as a colorless oil.
¹ H-NMR (CDCl ₃ ) δ: 1.27 (3H, t, J = 7.0 Hz), 1.55-2.36 (6H, m), 3.76 (1H, m), 3.86 (2H, s), 4.19 (2H, q , J = 7.0 Hz), 6.95 (1H, t, J = 4.0 Hz), 7.22-7.39 (5H, m).

Reference example C2
In the same manner as in Reference Example C1, ethyl 6- [N- (2,4-difluorophenyl) sulfamoyl] -1-cyclohexene-1-carboxylate (1 g) and (4-methoxyphenyl) methanethiol (893 mg) To give ethyl 6-[(4-methoxybenzyl) sulfanyl] -1-cyclohexene-1-carboxylate (848 mg) as a colorless oil.
¹ H-NMR (CDCl ₃ ) δ: 1.28 (3H, t, J = 7.0 Hz), 1.57-2.32 (6H, m), 3.74 (1H, m), 3.80 (3H, s), 3.82 (2H, s ), 4.20 (2H, q, J = 7.0 Hz), 6.84 (2H, d, J = 8.4 Hz), 6.94 (1H, t, J = 4.0 Hz), 7.29 (2H, d, J = 8.4 Hz).

Reference Example C3
In the same manner as in Reference Example C1, ethyl 6- [N- (2,4-difluorophenyl) sulfamoyl] -1-cyclohexene-1-carboxylate (455 mg) and (2,4-difluorophenyl) methanethiol ( 421 mg) gave ethyl 6-[(2,4-difluorobenzyl) sulfanyl] -1-cyclohexene-1-carboxylate (185 mg) as a colorless oil.
¹ H-NMR (CDCl ₃ ) δ: 1.26 (3H, t, J = 7.0 Hz), 1.60-2.40 (6H, m), 3.78 (1H, m), 3.84 (2H, s), 4.18 (2H, q , J = 7.0 Hz), 6.76-6.88 (2H, m), 6.97 (1H, t, J = 4.4 Hz), 7.34-7.46 (1H, m).

Reference Example C4
According to the same procedure as in Reference Example C1, ethyl 6- [N- (2,4-difluorophenyl) sulfamoyl] -1-cyclohexene-1-carboxylate (835 mg) and (2-chloro-4-fluorophenyl) methane Reaction with thiol (853 mg) gave ethyl 6-[(2-chloro-4-fluorobenzyl) sulfanyl] -1-cyclohexene-1-carboxylate (625 mg) as a colorless oil.
¹ H-NMR (CDCl ₃ ) δ: 1.26 (3H, t, J = 7.0 Hz), 1.56-2.36 (6H, m), 3.82 (1H, m), 3.94 (2H, s), 4.19 (2H, q , J = 7.0 Hz), 6.96 (1H, td, J = 8.6 Hz, 2.6 Hz), 6.98 (1H, m), 7.12 (1H, dd, J = 8.6 Hz, 2.6 Hz), 7.46 (1H, dd, J = 8.6 Hz, 6.0 Hz).

Reference Example C5
When 3-pyranone (20.0 g) is reacted in the same manner as described in Tetrahedron, 1963, 19, 1625, ethyl 5-hydroxy-3,6-dihydro-2H-pyran-4 -Carboxylate (7.52 g) was obtained as a colorless oil.
¹ H-NMR (CDCl ₃ ) δ: 1.32 (3H, t, J = 7.2 Hz), 2.31-2.38 (2H, m), 3.79 (2H, t, J = 5.6 Hz), 4.14 (2H, t, J = 1.8 Hz), 4.24 (2H, q, J = 7.2 Hz), 11.85 (1H, s).
SIMS: 172 (M ⁺ ).

Reference Example C6
When ethyl 5-hydroxy-3,6-dihydro-2H-pyran-4-carboxylate (12.9 g) is reacted in the same manner as described in Tetrahedron, 1974, 30, page 3753, Ethyl 5-sulfanyl-3,6-dihydro-2H-pyran-4-carboxylate (12.0 g) was obtained as a pale blue oil.
¹ H-NMR (CDCl ₃ ) δ: 1.32 (3H, t, J = 7.2 Hz), 2.42-2.50 (2H, m), 3.70 (1H, s), 3.84 (2H, t, J = 5.6 Hz), 4.22 (2H, t, J = 2.2 Hz), 4.25 (2H, q, J = 7.2 Hz).
Elemental analysis value: Calculated as C ₈ H ₁₂ O ₃ S (%): C, 51.04; H, 6.43; S, 17.03.
Found (%): C, 50.99; H, 6.54; S, 16.91.

Reference Example C7
Sodium peroxoborate tetrahydrate (24.5 g) was added to acetic acid (130 ml) and heated to 50-55 ° C., to which ethyl 5-sulfanyl-3,6-dihydro-2H-pyran-4-carboxylate was added. A solution of (10.0 g) in acetic acid (30 ml) was added dropwise over 2 hours. The mixture was stirred at 50-55 ° C. for 3 hours, and the reaction solution was concentrated under reduced pressure. Acetonitrile (230 ml) was added to the residue, the mixture was stirred at room temperature for 2 days, and the resulting insoluble material was filtered off. The insoluble material was washed with acetonitrile (70 ml), and the filtrate and washing solution were combined and concentrated under reduced pressure. The residue was dissolved in acetonitrile (160 ml) and stirred at room temperature for 6 hours. The resulting insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. Diisopropyl ether (100 ml) was added to the residue, and the precipitated insoluble matter was filtered, and 4- (ethoxycarbonyl) -5,6-dihydro-2H-pyran-3-sulfonic acid contained a light yellow oily substance (inorganic matter) 27.6 g).
¹ H-NMR (DMSO-d ₆ ) δ: 1.19 (3H, t, J = 7.2 Hz), 2.17-2.21 (2H, m), 3.65 (2H, t, J = 5.5 Hz), 4.04 (2H, q , J = 7.2 Hz), 4.16 (2H, t, J = 2.4 Hz).

Reference Example C8
4- (Ethoxycarbonyl) -5,6-dihydro-2H-pyran-3-sulfonic acid (27.5 g) was dissolved in thionyl chloride (82.6 ml) and stirred at room temperature → 85 ° C. for 3 hours. The reaction solution was evaporated to dryness and the residue was dissolved in ethyl acetate (100 ml). To the obtained solution was added dilute brine (120 ml), and the mixture was separated. The ethyl acetate layer was washed twice with saturated brine (50 ml) and then dried over anhydrous sodium sulfate. The residue obtained by distilling off the solvent was purified by silica gel column chromatography (eluent: ethyl acetate / hexane = 1/7 → 1/5), and the desired product was concentrated under reduced pressure and then produced under freezing. The obtained crystals were washed with hexane to obtain ethyl 5- (chlorosulfonyl) -3,6-dihydro-2H-pyran-4-carboxylate (7.81 g) as pale yellow crystals.
¹ H-NMR (CDCl ₃ ) δ: 1.37 (3H, t, J = 7.2 Hz), 2.62-2.70 (2H, m), 3.87 (2H, t, J = 5.5 Hz), 4.34 (2H, q, J = 7.2 Hz), 4.53 (2H, t, J = 2.6 Hz).
Elemental analysis value: Calculated as C ₈ H ₁₁ ClO ₅ S (%): C, 37.73; H, 4.35.
Found (%): C, 37.64; H, 4.27.

[Reference Example D]
Reference Example D1
M-Chlorobenzoic acid (196 mg) was added to a solution of ethyl 6- (benzylsulfanyl) -1-cyclohexene-1-carboxylate (100 mg) obtained in Reference Example C1 in methylene chloride (3 ml) under ice-cooling, and room temperature. For 1 hour. A saturated aqueous sodium hydrogen carbonate solution (20 ml) was added to the reaction solution, and the mixture was extracted with ethyl acetate (20 ml × 2). The ethyl acetate layer was washed with saturated aqueous sodium hydrogen carbonate solution (20 ml), water (20 ml) and saturated brine (20 ml), and dried over anhydrous sodium sulfate. The solvent was distilled off, and the resulting residue was purified by flash silica gel chromatography (eluent: hexane → ethyl acetate / hexane = 1/30) and crystallized from hexane to obtain ethyl 6- (benzylsulfonyl). -1-Cyclohexene-1-carboxylate (Compound 86, 106 mg) was obtained as white crystals.
¹ H-NMR (CDCl ₃ ) δ: 1.34 (3H, t, J = 7.2 Hz), 1.41-2.50 (6H, m), 4.28 (2H, q, J = 7.2 Hz), 4.29 (1H, d, J = 13.8 Hz), 4.35 (1H, m), 4.55 (1H, d, J = 13.8 Hz), 7.37-7.45 (4H, m), 7.50-7.55 (2H, m).
Elemental analysis value: Calculated as C ₁₆ H ₂₀ O ₄ S0.5H ₂ O (%): C, 60.55; H, 6.67.
Actual value (%): C, 60.98; H, 6.32.

Reference example D2
By reacting ethyl 6-[(4-methoxybenzyl) sulfanyl] -1-cyclohexene-1-carboxylate (98 mg) obtained in Reference Example C2 by the same procedure as in Reference Example D1, ethyl 6-[( 4-Methoxybenzyl) sulfonyl] -1-cyclohexene-1-carboxylate (compound 87, 88 mg) was obtained as white crystals.
¹ H-NMR (CDCl ₃ ) δ: 1.34 (3H, t, J = 7.0 Hz), 1.42-2.50 (6H, m), 3.82 (3H, s), 4.21 (1H, d, J = 13.6 Hz), 4.28 (2H, q, J = 7.0 Hz), 4.31 (1H, m), 4.50 (1H, d, J = 13.6 Hz), 6.92 (2H, d, J = 8.8 Hz), 7.41 (1H, t, J = 3.6 Hz), 7.47 (2H, d, J = 8.8 Hz).
Elemental analysis value: Calculated as C ₁₇ H ₂₂ O ₅ S (%): C, 60.33; H, 6.55.
Actual value (%): C, 60.42; H, 6.58.

Reference Example D3
By reacting ethyl 6-[(2,4-difluorobenzyl) sulfanyl] -1-cyclohexene-1-carboxylate (161 mg) obtained in Reference Example C3 by the same operation method as in Reference Example D1, ethyl 6- [(2,4-Difluorobenzyl) sulfonyl] -1-cyclohexene-1-carboxylate (Compound 88, 134 mg) was obtained as white crystals.
¹ H-NMR (CDCl ₃ ) δ: 1.32 (3H, t, J = 7.0 Hz), 1.59-2.50 (6H, m), 4.27 (2H, q, J = 7.0 Hz), 4.35 (1H, d, J = 14.0 Hz), 4.39 (1H, m), 4.51 (1H, d, J = 14.0 Hz), 6.83-6.96 (2H, m), 7.42 (1H, t, J = 4.0 Hz), 7.49-7.61 (1H , m).
Elemental analysis value: Calculated as C ₁₆ H ₁₈ F ₂ O ₄ S (%): C, 55.80; H, 5.27.
Actual value (%): C, 55.95; H, 5.40.

Reference example D4
By reacting ethyl 6-[(2-chloro-4-fluorobenzyl) sulfanyl] -1-cyclohexene-1-carboxylate (509 mg) obtained in Reference Example C4 by the same operation method as Reference Example D1, 6-[(2-Chloro-4-fluorobenzyl) sulfonyl] -1-cyclohexene-1-carboxylate (Compound 89, 422 mg) was obtained as white crystals.
¹ H-NMR (CDCl ₃ ) δ: 1.32 (3H, t, J = 7.0 Hz), 1.55-2.52 (6H, m), 4.25 (2H, q, J = 7.0 Hz), 4.41 (1H, d, J = 5.6 Hz), 4.59 (2H, s), 7.03 (1H, td, J = 8.4 Hz, 2.6 Hz), 7.21 (1H, dd, J = 8.4 Hz, 2.6 Hz), 7.42 (1H, t, J = 4.0 Hz), 7.62 (1H, dd, J = 8.4 Hz, 6.2 Hz).
Elemental analysis value: Calculated as C ₁₆ H ₁₈ ClFO ₄ S (%): C, 53.26; H, 5.03.
Actual value (%): C, 53.08; H, 4.95.

Reference Example D5
Ethyl 6-[(2-chloro-4-fluorobenzyl) sulfonyl] -1-cyclohexene-1-carboxylate (Compound 89, 100 mg) obtained in Reference Example D4 was subjected to high performance liquid chromatography (CHIRALPAK AD; eluent: hexane). / Ethanol = 8/2), which is separated into two optical isomers, filtered through a 0.45 μm filter, concentrated, and crystallized from hexane to obtain ethyl (−)-6-[(2-chloro-4- Fluorobenzyl) sulfonyl] -1-cyclohexene-1-carboxylate (compound 90, 50 mg) and ethyl (+)-6-[(2-chloro-4-fluorobenzyl) sulfonyl] -1-cyclohexene-1-carboxylate (Compound 91, 49 mg) was obtained as white crystals.
Compound 90
¹ H-NMR (CDCl ₃ ) δ: 1.32 (3H, t, J = 7.0 Hz), 1.56-2.55 (6H, m), 4.26 (2H, q, J = 7.0 Hz), 4.42 (1H, d, J = 5.6 Hz), 4.59 (2H, s), 7.03 (1H, td, J = 8.6 Hz, 2.4 Hz), 7.21 (1H, dd, J = 8.6 Hz, 2.4 Hz), 7.42 (1H, t, J = 4.2 Hz), 7.61 (1H, dd, J = 8.6 Hz, 6.0 Hz).
Elemental analysis value: Calculated as C ₁₆ H ₁₈ ClFO ₄ S (%): C, 53.26; H, 5.03.
Found (%): C, 53.24; H, 4.85.
[α] _D ²⁰ -97.0 ° (c = 0.5, in methanol).
Compound 91
¹ H-NMR (CDCl ₃ ) δ: 1.32 (3H, t, J = 7.0 Hz), 1.56-2.55 (6H, m), 4.26 (2H, q, J = 7.0 Hz), 4.42 (1H, d, J = 6.2 Hz), 4.59 (2H, s), 7.03 (1H, td, J = 8.6 Hz, 2.4 Hz), 7.21 (1H, dd, J = 8.6 Hz, 2.4 Hz), 7.42 (1H, t, J = 4.4 Hz), 7.60 (1H, dd, J = 8.6 Hz, 6.0 Hz).
Elemental analysis value: Calculated as C ₁₆ H ₁₈ ClFO ₄ S (%): C, 53.26; H, 5.03.
Actual value (%): C, 53.29; H, 4.82.
[α] _D ²⁰ + 95.0 ° (c = 0.5, in methanol).

Reference Example D6
2,4-Difluoroaniline (0.45 g) was dissolved in ethyl acetate (10 ml), triethylamine (0.55 mg) was added to the resulting solution under ice cooling, and the ethyl 5- (chloro chloride) obtained in Reference Example C8 was further added. A solution of sulfonyl) -3,6-dihydro-2H-pyran-4-carboxylate (0.69 g) in ethyl acetate (4 ml) was added dropwise. The reaction solution was stirred under a nitrogen stream at 0 ° C. for 30 minutes and further at room temperature for 5.8 hours. The reaction mixture was diluted with ethyl acetate and washed successively with water (50 ml), 0.5N hydrochloric acid (50 ml), water (50 ml × 2), and saturated brine (50 ml). The ethyl acetate layer was dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (eluent: ethyl acetate / hexane = 1/2). The target fraction was concentrated under reduced pressure, and the residue was crystallized from a mixture of ethyl acetate and diisopropyl ether. Ethyl 3-[(2,4-difluorophenyl) sulfamoyl] -3,6-dihydro-2H-pyran-4- Carboxylate (Compound 92; 0.57 g) was obtained as white crystals.
¹ H-NMR (DMSO-d ₆ ) δ: 1.14 (3H, t, J = 7.0 Hz), 3.69 (1H, dd, J = 12.8 Hz, 3.0 Hz), 4.08 (2H, q, J = 7.0 Hz) , 4.25 (2H, s), 4.33 (1H, d, J = 1.8 Hz), 4.41-4.48 (1H, m), 7.00-7.05 (1H, m), 7.12 (1H, br), 7.22-7.33 (1H , m), 7.43-7.55 (1H, m), 9.82 (1H, s).
Elemental analysis value: Calculated as C ₁₄ H ₁₅ F ₂ NO ₅ S (%): C, 48.41; H, 4.35; N, 4.03.
Found (%): C, 48.47; H, 4.35; N, 3.96.

Reference Example D7
By the same procedure as in Reference Example D6, ethyl 5- (chlorosulfonyl) -3,6-dihydro-2H-pyran-4-carboxylate (0.70 g) obtained in Reference Example C8 and 2-chloro-4- When reacted with fluoroaniline (0.52 g) ethyl 3-[(2-chloro-4-fluorophenyl) sulfamoyl] -3,6-dihydro-2H-pyran-4-carboxylate (compound 93; 0.54 g) Was obtained as white crystals.
¹ H-NMR (DMSO-d ₆ ) δ: 1.11 (3H, t, J = 7.0 Hz), 3.72 (1H, dd, J = 12.8 Hz, 3.0 Hz), 4.07 (2H, q, J = 7.0 Hz) , 4.15-4.25 (2H, m), 4.37 (1H, d, J = 2.2 Hz), 4.46-4.55 (1H, m), 7.15 (1H, br), 7.22-7.26 (1H, m), 7.46-7.59 (2H, m), 9.68 (1H, s).
Elemental analysis: Calculated as C ₁₄ H ₁₅ ClFNO ₅ S (%): C, 46.22; H, 4.16; N, 3.85.
Found (%): C, 46.35; H, 4.11; N, 3.73.

  Specific examples of the compound of the present invention that can be synthesized in the same manner as in the above Reference Examples are shown in Table 6 and Table 7, but the present invention is not limited to the compounds exemplified in Table 6 and Table 7.

[Example 1]

  11 g of Compound 72 was dissolved in 220 g of soybean oil, and 13.2 g of egg yolk lecithin and 2.2 g of dimyristoylphosphatidylglycerol were dissolved. 24.7 g of glycerin was dissolved in distilled water, and an acetic acid buffer was mixed and dissolved so that the final concentrations were 11.2 mM acetic acid and 8.8 mM sodium acetate. These were mixed, coarsely emulsified, and then finely emulsified using a high-pressure homogenizer at a pressure of 8000 psi. The obtained emulsified composition is filled with 20 mL in a 20 mL vial, purged with nitrogen, sealed with a rubber stopper and a plastic cap, sterilized by autoclave at 121 ° C. or higher for 15 minutes or longer, and the emulsified composition having the composition of Formula 1 above I got a thing.

  Next, as a control, 17 g of Compound 72 was dissolved in 340 g of soybean oil, and 20.4 g of egg yolk lecithin and 3.4 g of dimyristoylphosphatidylglycerol were dissolved. 38.25 g of glycerin was dissolved in distilled water. These were mixed, coarsely emulsified, and then finely emulsified using a high-pressure homogenizer at a pressure of 8000 psi. The obtained emulsified composition is filled with 20 mL in a 20 mL vial, then purged with nitrogen, sealed with a rubber stopper and a plastic cap, autoclaved at 121 ° C. or higher for 15 minutes or longer, and emulsified with the composition of Control Formula 2 above. A composition was obtained.

[Example 2]
The emulsified compositions of Formula 1 and Control Formula 2 obtained in Example 1 were stored at 25 ° C., and properties, pH, and average particle diameter were measured over time. The particle size was measured with a Malvern Mastersizer S.
The results are shown in Table 9.

  In Formula 1 containing an acetate buffer, the pH did not change before and after sterilization, and even during long-term storage at 25 ° C., the pH hardly changed, and Formula 1 was stable in terms of properties, pH, and average particle size. In Control Formula 2, the pH decreased from 4.6 to 4.0 before and after sterilization, and further decreased to 3.6 by storage at 25 ° C. for 3 months. The emulsion composition is destabilized due to a decrease in pH, and storage for 6 months at 25 ° C. causes phase separation between the dispersed phase particles and the water in which the dispersed phase particles are dispersed. Increased to 0.8 μm. Thus, it became possible to improve the pH fall at the time of sterilization and the pH fall at the time of long-term storage by mix | blending an acetate buffer with the emulsified composition containing Compound 72.

[Example 3]

  600 g of compound 72 was dissolved in 12 kg of soybean oil, and 720 g of purified egg yolk lecithin and 120 g of dimyristoyl phosphatidylglycerol were dissolved at 50 to 60 ° C. 1350 g of glycerin was dissolved in 20 kg of distilled water, and 40.35 g of glacial acetic acid and 71.85 g of sodium acetate trihydrate were mixed and dissolved at 50 to 60 ° C. These were mixed, made up to 60 L with distilled water, and coarsely emulsified for 5 minutes using a homogenizer polytron. Next, the mixture was finely emulsified using a high-pressure homogenizer at a pressure of 8000 psi and 8 passes. Compound 72 was dissolved and emulsified under a nitrogen stream. The obtained emulsified composition was filtered through a membrane filter having a pore size of 4.5 μm, filled with 20 mL in a 20 mL vial, purged with nitrogen, and sealed with a rubber stopper and a plastic cap. This was autoclaved at 121 ° C. or higher for 15 minutes or longer to obtain an emulsified composition formulation 3 having the above composition.

  Next, as a control, 600 g of Compound 72 was dissolved in 12 kg of soybean oil, and 720 g of purified egg yolk lecithin and 120 g of dimyristoylphosphatidylglycerol were dissolved at 50 to 60 ° C. 1350 g of glycerin was mixed and dissolved at 50-60 ° C. in 35 kg of distilled water. These were mixed, made up to 60 L with distilled water, and coarsely emulsified for 5 minutes using a homogenizer polytron.

  Next, the mixture was finely emulsified using a high-pressure homogenizer at a pressure of 8000 psi and 8 passes. Compound 72 was dissolved and emulsified under a nitrogen stream. The obtained emulsified composition was filtered with a membrane filter having a pore size of 5 μm, filled with 20 mL in a 20 mL vial, purged with nitrogen, and sealed with a rubber stopper and a plastic cap. This was autoclaved at 121 ° C. or higher for 15 minutes or longer to obtain a control formulation 4 of an emulsified composition having the above composition.

[Example 4]
The emulsion compositions of Formulation 3 and Control Formulation 4 obtained in Example 3 were stored at 25 ° C., and properties, pH, and average particle diameter were measured over time. The average particle size of formulation 3 was measured by Malvern Mastersizer 2000, and control formulation 4 was measured by Malvern Mastersizer S.

  The results are shown in Table 11. In Formula 3 containing an acetate buffer, the pH was constant before and after emulsification sterilization, the pH did not decrease even after long-term storage at 25 ° C. for 18 months, and the properties and average particle size remained unchanged and very stable. .

  In Control Formula 4, the pH dropped after storage at 25 ° C. for 3 months, and after storage for 6 months, free oil droplets were observed on the surface of the emulsified composition, making the properties unsuitable and increasing the average particle size to 3.6 μm. . Therefore, by adding a 20 mM acetate buffer to the emulsified composition containing Compound 72 in this way, an emulsified composition whose pH does not decrease during preparation, sterilization, or long-term storage can be obtained. It was. Thereby, it became possible to prepare a remarkably stable emulsion composition.

[Example 5]
In order to prepare a 25 mL total formulation containing various buffers at the same ratio as Control Formula 2, various concentrations of buffer were added and dissolved in the aqueous phase consisting of glycerin and distilled water. The composition of each buffer is as follows: acetic acid buffer: acetic acid and sodium acetate; lactic acid buffer: lactic acid and sodium lactate; citrate buffer: citric acid and sodium citrate; phosphate-citrate buffer: monohydrogen phosphate Disodium and citric acid, phosphate buffer was composed of monosodium dihydrogen phosphate and disodium monohydrogen phosphate, and carbonate buffer was composed of sodium carbonate and sodium bicarbonate, and were blended in the concentrations shown in Tables 12-15. Next, compound 72, egg yolk lecithin and dimyristoyl phosphatidylglycerol were dissolved in soybean oil. These were mixed, and after rough emulsification with a homogenizer, an emulsified composition was prepared with a sonicator. The obtained emulsified composition is filtered through a membrane filter having a pore size of 5 μm, filled with 20 mL in a 20 mL vial, purged with nitrogen, sealed with a rubber stopper and a plastic cap, and autoclaved at 121 ° C. or higher for 15 minutes or longer. The emulsion composition which mix | blends the buffering agent of this was obtained. The pH of each emulsified composition was investigated before and after autoclaving.

  The results are shown in Tables 12-15. By mixing an acetate buffer, a lactic acid buffer, a citrate buffer, and a phosphate-citrate buffer at 5 mM to 32 mM in the emulsified composition containing the compound 72, the pH hardly changes by high-pressure steam sterilization treatment. An emulsion composition having a pH of 4 to 5 was obtained.

  In addition, when the pH of the emulsion composition was adjusted to 6 by adding a buffer solution, even when using a phosphate buffer, carbonate buffer, or citrate buffer, the pH decreased significantly due to the high-pressure steam sterilization treatment. . With the carbonate buffer, the pH changed to about 7 before autoclaving.

[Example 6]

  500 g of compound 72 was dissolved in 10 kg of soybean oil, and 600 g of purified egg yolk lecithin and 100 g of dimyristoylphosphatidylglycerol were dissolved at 50 to 55 ° C. In about 10 kg of distilled water, 1125 g of glycerin was dissolved, and 33.63 g of glacial acetic acid and 59.88 g of sodium acetate trihydrate were mixed and dissolved at 50 to 55 ° C. These were mixed, made up to 50 L with distilled water, coarsely emulsified, and then finely emulsified with a high-pressure homogenizer at a pressure of 8000 psi and 8 passes. Compound 72 was dissolved and emulsified under a nitrogen stream. The obtained emulsified composition was filtered through a membrane filter having a pore size of 4.5 μm. The filtered emulsified composition was filled into a 20 mL vial, 20 mL, purged with nitrogen, and sealed with a rubber stopper and a plastic cap. Similarly, using the same filtered emulsified composition, a 20 mL vial was filled with 10 mL, a 20 mL vial was filled with 5 mL, a 10 mL vial was filled with 10 mL, and a 5 mL vial was filled with 5 mL. Sealed with a stopper and a plastic cap. These were subjected to autoclave sterilization at 121 ° C. or higher for 15 minutes or longer to obtain an emulsion composition formulation 5 having the above composition and different vial size and filling amount.

[Example 7]
The pH and average particle size of each emulsion composition of Formulation 5 obtained in Example 6 were investigated before and after autoclaving. The average particle size was measured with a Malvern Mastersizer 2000.

  The results are shown in Table 17. Regardless of vial size and fill volume, Formulation 6 containing acetate buffer was very stable with a constant pH before and after sterilization, no change in average particle size.

[Example 8]

  In 100 kg of soybean oil, 5000 g of Compound 72, 6000 g of purified egg yolk lecithin and 1000 g of dimyristoylphosphatidylglycerol were dissolved at 50 to 55 ° C. In distilled water, 11250 g of glycerin, 336.3 g of glacial acetic acid, and 598.8 g of sodium acetate trihydrate were mixed and dissolved at 50 to 55 ° C. These were mixed and made up to 500 L with distilled water. After rough emulsification, the mixture was finely emulsified with a high pressure homogenizer at a pressure of 8000 psi and 6 passes. Compound 72 was dissolved and emulsified under a nitrogen stream. The obtained emulsified composition was filtered through a membrane filter having a pore size of 4.5 μm. The filtered emulsion composition was filled into 10 mL vials with 10 mL and 10 mL vials with 5 mL, purged with nitrogen, and sealed with rubber stoppers and plastic caps. These were subjected to autoclave sterilization at 121 ° C. or higher for 15 minutes or longer to obtain an emulsion composition formulation 6 having the above composition and different filling amount.

[Example 9]
The pH and average particle size of each emulsion composition of Formulation 6 obtained in Example 8 were investigated before and after autoclaving. The average particle size was measured with a Malvern Mastersizer 2000.

  The results are shown in Table 19. Regardless of the filling amount, the formulation 6 containing an acetate buffer had a constant pH before and after sterilization, the average particle size did not change, and was very stable.

Comparative Example 1
In order to prepare a total formulation of 25 mL containing sodium hydroxide at various concentrations as a pH adjuster in the same ratio as in Control Formula 2, the final concentration of sodium hydroxide was 0 in the aqueous phase consisting of glycerin and distilled water. , 0.5, 0.75, 1, 1.5, and 2.0 mM, respectively. Next, compound 72, egg yolk lecithin and dimyristoyl phosphatidylglycerol were dissolved in soybean oil. These were mixed, and after rough emulsification with a homogenizer, an emulsified composition was prepared with a sonicator. The obtained emulsified composition was filtered with a membrane filter having a pore size of 5 μm, filled with 20 mL in a 20 mL vial, purged with nitrogen, sealed with a rubber stopper and a plastic cap, autoclaved at 121 ° C. or higher for 15 minutes or longer, pH The emulsion composition which mix | blends sodium hydroxide of various density | concentration as a regulator was obtained. The pH of each emulsified composition was investigated before and after autoclaving.

  The results are shown in Table 20. The emulsified composition containing Compound 72 showed a significant pH drop after sterilization when all concentrations of sodium hydroxide were added, including no compound.

  As is clear from the above explanation, since the pH of the emulsion composition of the present invention is adjusted to about 3.7 to about 5.5 by blending a buffering agent, even after sterilization with an autoclave or the like, In addition, even after storage for a long period of time, the pH of the emulsion composition and the average particle diameter of the dispersed phase particles hardly change and are stable. Therefore, the emulsified composition of the present invention and the compound which is the main component of the emulsified composition or a salt thereof or a prodrug thereof have excellent stability. Further, even after the emulsion composition of the present invention is sterilized by an autoclave or the like and stored for a long period of time, no visible oil droplets are observed, that is, the dispersed phase particles and the dispersed phase particles are dispersed. The water is stable without phase separation.

  In addition, since the emulsion composition of the present invention can be adjusted to a pH of about 3.7 to about 5.5 by adding a buffering agent to form a stable emulsion composition, An optimum pH can be selected according to other conditions such as stability. Therefore, even when there are other conditions that can be overcome by adjusting the pH in the range of about 3.7 to about 5.5, such as when affecting the stability of the emulsified composition, select the pH adjustment. Thus, an emulsified composition suitable for various conditions can be obtained.

  Furthermore, the emulsified composition of the present invention exhibits a long-term stability of 24 months, which is over 18 months of the typical use period for emulsion formulations.

  This application is based on patent application No. 2005-131807 filed in Japan, the contents of which are incorporated in full herein.

Claims (25)

(A) Ethyl (6R) -6- [N- (2-chloro-4-fluorophenyl) sulfamoyl] cyclohex-1-ene-1-carboxylate as a stable compound in the acidic region,
d-ethyl 6- [N- (2,4-difluorophenyl) sulfamoyl] cyclohex-1-ene-1-carboxylate,
Ethyl 6- [N- (2-chlorophenyl) sulfamoyl] cyclohex-1-ene-1-carboxylate,
Ethyl 6- [N- (2-chloro-4-methylphenyl) sulfamoyl] cyclohex-1-ene-1-carboxylate,
Ethyl 6-[(2-chloro-4-fluorobenzyl) sulfonyl] -1-cyclohexene-1-carboxylate,
Ethyl (+)-6-[(2-chloro-4-fluorobenzyl) sulfonyl] -1-cyclohexene-1-carboxylate, or ethyl 3-[(2-chloro-4-fluorophenyl) sulfamoyl] -3, 6-dihydro-2H-pyran-4-carboxylate, or a salt thereof,
A dispersed phase particle having an average particle size of 0.025 to 0.7 μm, comprising an oil component and an emulsifier;
(B) an acetic acid buffer that is a combination of acetic acid or glacial acetic acid and sodium acetate, a lactic acid buffer that is a combination of lactic acid and sodium lactate, a citrate buffer that is a combination of citric acid and sodium citrate, and 1 or 2 or more selected from the group consisting of a phosphate buffer that is a combination of monosodium dihydrogen phosphate and disodium hydrogen phosphate, and a buffer having a concentration of 100 mM or less, and (C) water An emulsified composition whose pH is adjusted to 3.7 to 5.5.   The composition according to claim 1, further comprising an anionic synthetic phospholipid as an emulsifier.   Compounds that are stable in the acidic region are ethyl (6R) -6- [N- (2-chloro-4-fluorophenyl) sulfamoyl] cyclohex-1-ene-1-carboxylate, ethyl 6-[(2-chloro- 4-fluorobenzyl) sulfonyl] -1-cyclohexene-1-carboxylate, or ethyl (+)-6-[(2-chloro-4-fluorobenzyl) sulfonyl] -1-cyclohexene-1-carboxylate. The composition according to claim 1 or claim 2.   The compound stable in the acidic region is ethyl (6R) -6- [N- (2-chloro-4-fluorophenyl) sulfamoyl] cyclohex-1-ene-1-carboxylate. The composition in any one of.   The composition according to claim 1 or 2, wherein the acetate buffer is a combination of acetic acid or glacial acetic acid and sodium acetate.   The composition according to claim 1, which is an oil-in-water type.   The composition according to claim 1, wherein the dispersed phase particles have an average particle size of 0.05 to 0.4 μm.   The composition according to claim 7, wherein the dispersed phase particles and the water in which the dispersed phase particles are dispersed are stable without phase separation.   A composition according to claim 1 which is free of visible oil droplets.   The composition according to claim 1, wherein the oil component is vegetable oil.   The composition according to claim 10, wherein the vegetable oil is soybean oil.   The composition of claim 1, wherein the emulsifier is a phospholipid.   The composition according to claim 12, wherein the phospholipid is egg yolk lecithin or phosphatidylglycerol.   The composition of claim 2, wherein the anionic synthetic phospholipid is phosphatidylglycerol.   The composition according to claim 1, wherein the amount of the oil component is 1 to 30% by weight based on the whole composition.   The composition according to claim 1, wherein the amount of the emulsifier is 0.1 to 10% (W / V) based on the whole composition.   The composition according to claim 13 or 14, wherein the phosphatidylglycerol is dimyristoyl phosphatidylglycerol.   The composition according to claim 1, further comprising glycerin.   The composition according to claim 1 or 2, which is for injection.   The composition according to any one of claims 1 and 2, comprising 0.001 to 95% by weight of a compound which is stable in an acidic region with respect to the whole composition. (A) a compound which is stable in the acidic region according to claim 1,
A dispersed phase particle having an average particle size of 0.025 to 0.7 μm, comprising an oil component and an emulsifier;
(B) an acetic acid buffer that is a combination of acetic acid or glacial acetic acid and sodium acetate, a lactic acid buffer that is a combination of lactic acid and sodium lactate, a citrate buffer that is a combination of citric acid and sodium citrate, and 1 or 2 or more selected from the group consisting of a phosphate buffer that is a combination of monosodium dihydrogen phosphate and disodium hydrogen phosphate, and a buffer having a concentration of 100 mM or less, and (C) water A method for producing an emulsified composition, comprising adjusting the pH to 3.7 to 5.5.   The production method according to claim 21, wherein the emulsified composition further contains an anionic synthetic phospholipid as an emulsifier.   The production method according to claim 21, wherein the stability of the pH of the emulsified composition and the particle size of the dispersed phase particles during autoclave sterilization is improved. A method for long-term stabilization of an emulsified composition, wherein the emulsified composition is (A) a compound that is stable in the acidic region according to claim 1,
A dispersed phase particle having an average particle size of 0.025 to 0.7 μm, comprising an oil component and an emulsifier;
(B) an acetic acid buffer that is a combination of acetic acid or glacial acetic acid and sodium acetate, a lactic acid buffer that is a combination of lactic acid and sodium lactate, a citrate buffer that is a combination of citric acid and sodium citrate, and 1 or 2 or more selected from the group consisting of a phosphate buffer that is a combination of monosodium dihydrogen phosphate and disodium hydrogen phosphate, and a buffer having a concentration of 100 mM or less, and (C) water A long-term stabilization method comprising adjusting the pH of the emulsion composition to 3.7 to 5.5.   The long-term stabilization method according to claim 24, further comprising adding an anionic synthetic phospholipid as an emulsifier to the emulsified composition.